1-Hydroxymethyl-1-oxo-prostane derivatives of the F1 series

ABSTRACT

Derivatives, analogs, and congeners of prostane having a 1-(hydroxymethyl)-1-oxo-prostane structure in the F 1  series.

BACKGROUND OF THE INVENTION

Applicant is not aware of any prior art references which, in hisjudgment as one skilled in the prostaglandin art, would anticipate orrender obvious the novel compounds of the instant invention; however,for the purpose of fully developing the background of the invention andestablishing the state of the requesite art, the following referencesare set forth: U.S. Pat. Nos. 4,028,396; 3,849,487, and 3,813,433;Belgium Patent Specification No. 781,978; Japanese Patent SpecificationNo. 1004-151; Netherlands Patent Specification No. 7,203,126; and WestGerman Patent Specification No. 2505-303.

BRIEF SUMMARY OF THE INVENTION

The first embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR1## wherein X is a divalent moietyselected from the group consisting of ##STR2## f is an integer from 5 to7, inclusive; R₃ is selected from the group consisting of hydrogen andhydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethylene andtrans-vinylene; R₁ is a radical selected from the group consisting of##STR3## wherein R₄ is selected from the group consisting of hydrogenand methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆is selected from the group consisting of C₃ -C₅ alkyl, R₇ is selectedfrom the group consisting of C₂ -C₄, R₈ is selected from the groupconsisting of C₁ -C₂ alkyl, R₁₁ is selected from the group consisting ofC₃ -C₇ alkyl, p is an integer from 0 to 3, and q is 1 or 2; the racemicmixture thereof; and the mirror image thereof.

A first preferred embodiment of the first embodiment consists of thesecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR4## and X is the divalent moiety##STR5##

A second preferred embodiment of the first embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR6## wherein R is as previouslydefined; and X is the divalent moiety ##STR7##

A first further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR8## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previouslydefined.

A second further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁ R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR9## wherein R₇, p and q are as previously defined.

A still further preferred embodiment of the second further preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR10## wherein p and q are as previously defined.

A first further preferred embodiment of the second preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR11## wherein R₄, R₅, R₆, R₈, and R₁₁ are aspreviously defined.

A second further preferred embodiment of the second preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR12## wherein R₇, p and q are as previously defined.

A still further preferred embodiment of the second further preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R is a moiety selected from the groupconsisting of ##STR13## wherein p and q are as previously defined.

The second embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR14## wherein X is a divalent moietyselected from the group consisting of ##STR15## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of hydrogenand hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethyleneand trans-vinylene; R₁ is a radical selected from the group consistingof ##STR16## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR17##wherein R₄ is selected from the group consisting of hydrogen and methyl,R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selectedfrom the group consisting of C₂ -C₄, R₈ is selected from the groupconsisting of C₁ -C₂ alkyl, R₁₁ is selected from the group consisting ofC₃ -C₇ alkyl, p is an integer from 0 to 3, and q is 1 or 2; the racemicmixture thereof and the mirror image thereof.

A first preferred embodiment of the second embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR18## and X is the divalent moiety##STR19##

A second preferred embodiment of the second embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; and R₁ is the moiety ##STR20## wherein R is aspreviously defined; and X is the divalent moiety ##STR21##

A first further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR22## wherein R₄, R₅, R₆, R₈ and R₁₁ are as previouslydefined.

A second further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR23## wherein R₇, p and q are as previously defined.

A still further preferred embodiment of the second further preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR24## wherein p and q are as previously defined.

The third embodiment of the inventor is represented by an opticallyactive compound of the formula: ##STR25## wherein X is a divalent moietyselected from the group consisting of ##STR26## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of hydrogenand hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethyleneand trans-vinylene; R is a radical selected from the group consisting of##STR27## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR28##wherein R₆ is selected from the group consisting of C₃ -C₆ alkyl, R₇ isselected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected fromthe group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the groupconsisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consistingof C₁ -C₄ alkyl; the racemic mixture thereof; and the mirror imagethereof.

A first preferred embodiment of the third embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR29## and X is the divalent moiety##STR30##

A second preferred embodiment of the third embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; and R₁ is the moiety ##STR31## wherein R is aspreviously defined; and X is the divalent moiety ##STR32##

A first further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined, and R₂ is the moiety selected from the groupconsisting of ##STR33## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previouslydefined.

A second further embodiment of the first preferred embodiment consistsof those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previouslydefined; and R₂ is a moiety selected from the group consisting of##STR34## wherein R₇ is as previously defined.

A still further preferred embodiment of the second further preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR35## wherein R₇ is as previously defined.

A first still further preferred embodiment of the first furtherpreferred embodiment consists of those compounds wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR36## wherein R₆, R₁₁ and R₁₂ are aspreviously defined.

A second still further preferred embodiment of the first furtherpreferred embodiment consists of those compounds wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR37## wherein R₁₀ and R₁₁ are aspreviously defined.

A first further preferred embodiment of the second preferred embodimentconsists of the compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined, and R₂ is a moiety selected from the groupconsisting of ##STR38## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previouslydefined.

A second further preferred embodiment of the second preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR39## wherein R₇ is as previously defined.

A still further preferred embodiment of the second further preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR40## wherein R₇ is as previously defined.

A first still further preferred embodiment of the first preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR41## wherein R₆, R₁₁ and R₁₂ are as previouslydefined.

A second still further preferred embodiment of the first furtherpreferred embodiment consists of those compounds wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR42## wherein R₁₀ and R₁₁ are aspreviously defined.

The fourth embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR43## wherein X is a divalent moietyselected from the group consisting of ##STR44## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of hydrogenand hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethyleneand trans-vinylene; R₁ is a radical selected from the group consistingof ##STR45## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR46##wherein R₆ is selected from the group consisting of C₃ -C₆ alkyl, R₇ isselected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected fromthe group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the groupconsisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consistingof C₁ -C₄ alkyl; the racemix mixture thereof; and the mirror imagethereof.

A first preferred embodiment of the forth embodiment consists of thosecompounds wherein f, R₂, and R₃ are as previously defined C₁₃ -C₁₄ istrans-vinylene; and R₁ is the moiety. ##STR47## and X is the divalentmoiety ##STR48##

A second preferred embodiment of the fourth embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR49## wherein R is as previouslydefined; and X is the divalent moiety ##STR50##

A first further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁ R₃, C₁₃ -C₁₄, X and f are aspreviously defined, and R₂ is a moiety selected from the groupconsisting of ##STR51## wherein R₆, R₁₀, R₁₁ and R₁₂ are as previouslydefined.

A second further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR52## wherein R₇ is as previously defined.

A still further preferred embodiment of the second further preferredembodiment consists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and fare as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR53## wherein R₇ is as previously defined.

A first still further preferred embodiment of the first furtherpreferred embodiment consists of those compounds wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR54## wherein R₆, R₁₁ and R₁₂ are aspreviously defined.

A second still further preferred embodiment of the first furtherpreferred embodiment consists of those compounds wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR55## wherein R₁₀ and R₁₁ are aspreviously defined.

The fifth embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR56## wherein X is a divalent moietyselected from the group consisting of ##STR57## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of hydrogenand hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethyleneand trans-vinylene; R is a radical selected from the group consisting of##STR58## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR59##wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ isselected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selectedfrom the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof;and the mirror image thereof.

A first preferred embodiment of the fifth embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety. ##STR60## and X is the divalent moiety##STR61##

A second preferred embodiment of the fifth embodiment consists of thosecompounds wherein f, R₂, and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; and R₁ is the moiety ##STR62## wherein R is as firstpreviously defined; and X is the divalent moiety ##STR63##

A further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄ and f are aspreviously defined and R₂ is a moiety selected from the group consistingof ##STR64## wherein R₁₁ is as previously defined.

A second further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR65## wherein R₆ and R₈ are as previously defined.

A first further preferred embodiment of the second preferred embodimentconsists of those compounds wherein R₁ R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR66## wherein R₁₁ is as previously defined.

A second further preferred embodiment of the second preferred embodimentconsists of those compounds wherein R₁ R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR67## wherein R₆ and R₈ are as previously defined.

The sixth embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR68## wherein X is a divalent moietyselected from the group consisting of ##STR69## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of hydrogenand hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethyleneand trans-vinylene; R₁ is a radical selected from the group consistingof ##STR70## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR71##wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ isselected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selectedfrom the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof;and the mirror image thereof.

A first preferred embodiment of the sixth embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR72## and X is the divalent moiety##STR73##

A second preferred embodiment of the sixth embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR74## wherein R is as previouslydefined; and X is the divalent moiety ##STR75##

A first further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁ R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR76## wherein R₁₁ is as previously defined.

A second further preferred embodiment of the first preferred embodimentconsists of those compounds wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR77## wherein R₆ and R₈ are as previously defined.

The seventh embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR78## wherein X is a divalent moietyselected from the group consisting of ##STR79## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of hydrogenand hydroxyl; C₁₃ -C₁₄ is selected from the group consisting of ethyleneand trans-vinylene; R is a radical selected from the group consisting of##STR80## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR81##wherein X is a divalent radical selected from the group consisting of##STR82## wherein R₅ is selected from the group consisting of C₁ -C₇alkyl, hydrogen and a phenoxy group optionally substituted from thegroup consisting of halogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is atrivalent radical selected from the group consisting of ##STR83## Z is adivalent radical selected from the group consisting of --O and --CH₂ --,m is zero or an integer from 1 to 4, inclusive, n is zero or an integerfrom 1 to 4 inclusive, with the proviso that the sum of m and n has thevalue of 1 to 4, s is zero or the integer 1, t is selected from thegroup consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl,methoxy and t-butyl; the racemic mixture thereof; and the mirror imagethereof.

A first preferred embodiment of the seventh embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istransvinylene; R₁ is the moiety ##STR84## and X is the divalent moiety##STR85##

A second preferred embodiment of the seventh embodiment consists ofthose compounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄is trans-vinylene; R₁ is the moiety ##STR86## wherein R is as previouslydefined; and X is the divalent moiety ##STR87##

The eighth embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR88## wherein X is a divalent moietyselected from the group consisting of ##STR89## f is an integer from 5to 7, inclusive; R₃ is selected from the group consisting of ethyleneand trans-vinylene; R₁ is a radical selected from the group consistingof ##STR90## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR91##wherein X is a divalent radical selected from the group consisting of##STR92## wherein R₅ is selected from the group consisting of C₁ -C₇alkyl, hydrogen and a phenoxy group optionally substituted from thegroup consisting of halogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is atrivalent radical selected from the group consisting of ##STR93## Z is adivalent radical selected from the group consisting of --O and --CH₂ --,m is zero or an integer from 1 to 4, inclusive, n is zero or an integerfrom 1 to 4, inclusive, with the proviso that the sum of m and n has thevalue of 1 to 4, s is zero or the integer 1, t is selected from thegroup consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl,methoxy and t-butyl; the racemic mixture thereof; and the mirror imagethereof.

A first preferred embodiment of the eight embodiment consists of thosecompounds wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR94## and X is the divalent moiety##STR95## A second preferred embodiment of the eight embodiment consistsof those compounds wherein f, R₂ and R₃ are as previously defined; C₁₃-C₁₄ is trans-vinylene; R₁ is the moiety ##STR96## and X is the divalentmoiety ##STR97##

DESCRIPTION OF THE INVENTION

The compounds of this invention are administered in various ways forvarious purposes, e.g., intravenously, intramuscularly, subcutaneously,orally, intravaginally, rectally, bucally, sublingually, topically andin the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsuspensions are preferred. For subcutaneous or intramuscular injection,sterile suspensions of the compounds in aqueous or non-aqueous media areused. Tablets, capsules, and liquid preparations such as syrups,elixirs, and simple solutions, with the usual pharmaceutical carriersare used for oral or sublingual administration. For rectal or vaginaladministration, suppositories prepared as known in the art are used. Fortissue implants, a sterile tablet or silicone rubber capsule or otherobject containing or impregnated with the substance is used. On certainoccasions it may be advantageous to administer the compounds of thisinvention as clathrate compounds with substances such as α-cyclodextrin.

The prostaglandins are a family of closely related compounds which havebeen obtained from various animal tissues and which stimulate smoothmuscle, lower arterial blood pressure, antagonize epinephrine-inducedmobilization of free fatty acids, and have other pharmacological andautopharmacological effects in mammals. See Bergstom, et al., J. Biol.Chem., 238, 3555 (1963 ) and Horton, Experientia, 21, 113 (1965) andreferences cited therein. All of the so called natural prostaglandinsare derivatives of prostanoic acid: ##STR98## The hydrogen atomsattached to C-8 and C-12 are in trans-configuration. The naturalprostaglandins represent only one of the possible optical isomers. Thecompounds of this invention include all possible optical isomers andracemates.

The configuration of substituents on the prostaglandin molecule aredesigned to be in the α-configuration if they lie beneath the plane ofthe molecule as drawn above and are designated with a - - - - bond.Those substituents which lie above the plane of the molecule as drawnabove are designated β and are represented by a bond.

The compounds of this invention which have the structure as shown informula (A) wherein T, Z, R₃, Y, m, n, s and X are as herein abovedefined are said to be in the same configuration as the naturalprostaglandins with respect to the configurations at C₈, C₁₁ and C₁₂ andare designated by the prefix nat. The enantiomer, represented by formula(B) is said to be in the mirror image or ent configuration. Asubstituent at C₁₁ drawn with a dotted line (C₁₁ - - - - R₃) is said tohave an α configuration; a solid line (C₁₁ -R₃) indicates a βconfiguration. The configuration at Y and X will be expressed in termsof R and S as is understood in the art. For example, the compoundrepresented by formula (C) is namednat-15S,16S-11α,15-dihydroxy-1-(hydroxymethyl)-1,9-dioxo-15,-16-trimethylene-13-trans-prostene;its enantiomer (formula D) is namedent-15R,16R-11α,15-dihydroxy-1-(hydroxymethyl)-1,9-dioxo-15,16-trimethylene-13-trans-prostene.The racemate [ 1:1 mixture of (C) and (D)] is named nat-15S,16S-(andent-15R,16R)11α,15-dihydroxy-1-hydroxymethyl)-1,9-dioxo-15,16-trimethylene-13-trans-prostene.In a similar manner, the compounds represented by formulae (E) to (J)have the configuration shown below. ##STR99##

In each of the above formulae (C to J) the hydroxy group at C₁₁ is named"-11α-hydroxy".

The novel compounds of this invention can be prepared by a novel1,4-conjugate-addition procedure involving treatment of the etherblocked cyclopentenone such as (129) or (111) with a lithio-cupratereagent such as (117), (118), or (119) prepared as illustrated inFlowsheets A thru N.

The 1,4-conjugate-addition procedure is described hereinbelow inFlowsheet N. The preparation of the various requisite1-iodo-trans-1-alkenyl or 1-tributylstannyl-trans-1-alkenyl derivativeis illustrated in Flowsheets A-H and the novel and important methods ofpreparation of the 4-hydroxycyclopentenones embracing the1-(hydroxymethyl)-1-oxo α chain is described in connection withFlowsheets I-M. ##STR100## wherein f' is one or two inclusive.

In accordance with the scheme as outlined hereinabove in Flowsheet A,carbethoxycyclobutane or carbethoxycyclopentane is converted to itsenolate anion (2) by treatment with a strong base such as lithiumcyclohexylisopropylamide, prepared from the corresponding amine andn-butyl lithium (hexane solution) in a solvent, such as anhydroustetrahydrofuran, at very low temperatures, such as -78° C. The resultingenolate anion (2) is then alkylated with R₆ 3-X (3) to provide (4), theester group of which is reduced to alcohol (5) by reaction with 2equivalents of diisobutyl aluminum hydride, lithium aluminum hydride orthe like. Oxidation of alcohol (5) with dipyridine chromium oxidecomplex ["Reagents for Organic Synthesis", L. F. Fieser and M. Fieser,John Wiley and Sons, Inc., New York 4, 215 (1974], prepared in situ inmethylene chloride solution, provides the corresponding aldehyde (6),which can also be obtained directly from ester (4) by partial reductionwith one equivalent of diisobutyl aluminum hydride at -78° C., but theformer two-step procedure is preferable. Reaction of aldehyde (6) withlithium acetylide ethylene diamine complex provides the 3-hydroxy-1-alkyne (7), which is converted to its trimethylsilyl ether inthe usual manner. The silylated derivative is then treated withdisiamylborane (prepared in situ in tetrahydrofuran solution at ice bathtemperatures from 2-methyl-2-butene, sodium borohydride and borontrifluoride ethereate) and then anhydrous trimethylamine oxide. Theresulting solution and an iodine solution in tetrahydrofuran are thenadded simultaneously to an aqueous solution of sodium hydroxide to givethe 1-iodo-3-trimethylsilyloxy-4,4-methylene-1-alkene (8). Also, theabove sequences of reactions can be accomplished, as shown in FlowsheetA, using R₉ CH₂ X where R₉ is a phenyl group. ##STR101##

In accordance with the scheme as outlined hereinabove in Flowsheet B,1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne (9) is treated withn-butyllithium at -78° C. and then with a freshly prepared solution ofzinc iodide in anhydrous tetrahydrofuran, also at -78° C. Reaction ofaldehyde (10) with the resulting reagent then provides the4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11). This reaction procedeswith great stereoselectivity and the product (11) is in the erythroconfiguration. [For additional information concerning this reaction seethe examples which follow and F. Mercier, R. Epstein and S. Holland,Bull. Soc. Chim. France, 690 (1972)].

The tetrahydropyranyl group in (11) is removed on weak acid treatmentand the resulting erythro diol (12) can be reblocked by treating with anappropriate aldehyde or ketone ##STR102## in the presence of strong acidcatalyst in the usual way to give the ketal or acetal (13). Acetone is auseful ketone for this purpose and the product (13) is then a3,4-isopropylidenedioxy-1-alkyne. It is also possible to utilize silylblocking groups (introduced after removal of the 1-trimethylsilyl group)to ultimately give the vinyl iodides (16) or (17). Weak base treatmentof (13), for example heating for about one hour in refluxing methanolwith potassium carbonate, results in desilylation to give (14). The1-alkene (14) is converted to the corresponding 1-iodo-trans-1-alkene(15) by treatment with disiamylborane (prepared in situ intetrahydrofuran solution at ice bath temperatures form2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate)and then anhydrous trimethylamine oxide. The resulting solution and aniodine solution in tetrahydrofuran are then added simultaneously to anaqueous solution of sodium hydroxide to give (15).

For the preparation of the threo derivatives, the4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11) is acetylated to providethe corresponding 4-acetoxy derivative (18). The tetrahydropyranyl groupis preferentially hydrolized with weak acid to (19), which is thentosylated in the usual manner to afford theerythro-3-tosyloxy-4acetoxy-1-alkyene (20). Solvolysis of (20) underessentially neutral conditions by heating in aqueous tetrahydrofuran inthe presence of an insoluble acid-acceptor, such as calcium carbonate,results in inversion of C₃, furnishing thethreo-3-hydroxy-4-acetoxy-1-alkyne (21), which is then deblocked withaqueous base to give the threo-3,4-diol (22). Diol (22) is converted toan acetal or ketal (23) [or silyl derivatives as in (16) or (17)] andthence to the 1-iodo-trans-1-alkene (16) as described hereinabovewherein Ra is lower alkyl (C₁ to C₃).

For the preparation of the 16-alkoxyprostanoic acids of this invention,the erythro-4-hydroxy-3-tetrahydropyranyloxy-1-alkyene (11) isdesilylated by methanol-potassium carbonate treatment and the resulting(25) is alkylated to give the 4-alkoxy-3-tetrahyropyranyloxy-1-alkyne(26). A useful procedure for this last step involves treatment of (25)with a molar equivalent of sodium hydride to give the 4-alkoxide whichis then alkylated with the appropriate alkylating agent, for examplemethyl iodide. The 4-alkoxy-1-alkyne (26) is then converted to thecorresponding 1-iodo-trans-1-alkene (27) as described hereinabove forthe preparation of (15). If desired the tetrahydropyranyl blocking groupin (27) can be hydrolyzed (weak acid) and the ressulting free 3-olcorresponding to (27) converted to the 3-trimethylsilyloxy derivative(28), all in the usual manner wherein Ra is lower alkyl (C₁ to C₃).

For the threo series, the tetrahydropyranyl group inerythro-4-alkoxy-1-alkyne (26) is cleaved and the resulting3-hydroxy-4-alkoxy-1-alkyne (29) is tosylated to give theerythro-3-tosyloxy-4-alkoxy-1-alkyne (30). Sn₂ displacement reactionwith (30) with reagents such as tetrahydroammonium formate results ininversion to the threo derivative (31) saponification of which providesthreo-3-hydroxy-4-alkoxy-1-alkyne (32). Trimethylsilylation followed bythe vinyl iodide conversion procedure described hereinabove furnishesthe threo-1-iodo-1-alkene (33) wherein Rd is hydrogen or lower alkyl (C₁to C₃).

The 15-alkyl and/or 16-alkyl derivatives of this invention can beprepared by substituting ##STR103## for (9) and/or ##STR104## for (10)(R'₅ =lower alkyl of 1 to 3 carbons) in Flowsheet B.

In accordance with the procedure as outlined in Flowsheet C, an aldehyde(34) is treated with propargylic magnesium halide to form thehomopropargylic alcohol (35), which is converted to its trimethylsilylether in the usual manner. The silylated derivative is then treated withdisiamylborane (prepared in situ in tetrahydrofuran solution at ice bathtemperature from 2-methyl-2-butene, sodium borohydride and borontrifluoride ethereate) and then anhydrous trimethylamine oxide. Theresulting solution and an iodine solution in tetrahydrofuran are addedsimultaneously to a sodium hydroxide to give the1-iodo-4-trimethylsilyloxy-trans-1-alkene (36), precursors for16-hydroxy-prostaglandin.

The trimethylsilyl protecting group is removed with mild acid and theresulting vinyl iodide alcohol is oxidized with pyridiniumchlorochromate to provide the 1-iodo-4-oxo-trans-1-alkene (37), whichupon treatment with a Grignard reagent (R₁₃ MgX) provides the1-iodo-4-hydroxy-trans-1-alkene, which is silylated in the usual mannerto provide the silyl ether (38) wherein R'₁₁ is lower alkyl (C₃ to C₇)or lower alkenyl group (C₃ to C₅) and R₁₃ is vinyl, cyclopropyl orethyl. ##STR105##

A more preferred method for the preparation of vinyllithium precursor isalso described in Flowsheet C. Treatment of the requisite carboxylicacid (39a or 39) with the appropriate organolithium reagent (R₁₃ Li orR'₁₁ Li respectively), wherein R'₁₁ and R₁₃ are hereinabove defined,give the corresponding ketone (40) which upon treatment with propargylicmagnesium halide provides the homopropargylic alcohol (41) which isconverted to the trans vinylstannyl derivative by sequential treatmentwith chlorotrimethylsilane and tri-n-butyltin hydride. Treatment of thevinylstannyl reagent (42) with n-butyllithium at a temperature of -10°C. to -78° C. generates the corresponding vinyllithium reagent.##STR106##

In accordance with Flowsheet D hereinabove, the precurslors for other16-hydroxy prostaglandins are prepared by treating an appropritealdehyde or ketone (43) with a propargylic magnesium halide to yield therequisite homopropargylic alcohol (44). The alcohol is protected as atritylether (45) (for secondary alcohols) or as a trimethylsilylether(45) (for tertiary alcohols). These ethers are then converted to theappropriate trans-vinyliodide (46) by treatment with disiamylboranegenerated in situ from 2-methyl-2-butene, sodium borohydride, and boromtrifluoride, followed by treatment with trimethylamine oxide and theniodine and sodium hydroxide, wherein R₁₅ is hydrogen, methyl or ethyl; Zis O-C(C₆ H₅)₃ when R₁₅ is hydrogen and Z is O-Si)CH₃)3 when R₁₅ ismethyl or ethyl; R₁₄ is selected from the group comprising lower alkyl(C₃ to C₅), lower 1-alkenyl (C₃ to C₅), ##STR107## wherein R₇ isdescribed above with the proviso that when R₁₄ is ##STR108## then R₁₅must be hydrogen. ##STR109##

The preparation of the precursors for the synthesis of 16aryloxycongeners is described in accordance with Flowsheet E hereinabove. Thearyl esters (49) are prepared by esterifying the commercially availableacids or by treatment of ethyl bromoacetate with the approprite phenol.The ester (49) is carefully reduced to the aldehyde (50) which upontreatment with lithium acetylide provides the propargylic alcohol (51).Treatment of the alcohol (51) with chlorotrimethylsilane followed bytri-n-butyltin hydride furnishes the requisite vinylstannyl derivative(53). Similar treatment starting with substituted hydrocinnamaldehyde(50a) provides the respective vinylstannyl derivative (53a).

The preparation of the precursors for the synthesis of secondary15-hydroxy congeners are described in the literature. The preparation ofthe precursor for 15-methyl-15-hydroxy is described in Flowsheet Fhereinbelow. In accordance with Flowsheet F, an acid chloride, whereinR₅ is hereinabove defined, is treated with acetylene and aluminumtrichloride to provide the vinylchloride (55) which upon treatment withsodium iodide furnishes the vinyliodide (56). Treatment of (56) withmethylmagnesium halide followed by chlorotrimethylsilane gives therequisite protected vinyliodide (57). ##STR110##

The precursors for the novel compounds of this invention which have a βchain represented by Formuler K ##STR111## wherein s, y, m, n and X areherein above defined is shown in Flowsheet G and Flowsheet H. ##STR112##

In accordance with the scheme as outlined hereinabove in Flowsheet G aketone (58) is reacted with a Grignard reagent (59) such as acetylenemagnesium chloride (59, s=O) or propargyl magnesium bromide (59, s=1) togive the acetylenic alcohols (60). In those cases where X is not --CH₂-- two isomeric acetylenic alcohols are formed. These isomers can beseparated by procedures well known to the art including fractionalcrystallization, fractional distillation and various chromatographicprocedures. The individual isomers can then be carried through theremaining reactions outlined in Flowsheet G.

The acetylenic alcohol (60) is converted to its trimethylsilyl ether inthe usual manner. The silylated derivative (61) is then treated withdiisomaylborane (prepared in situ in tetrahydrofuran solution at icebath temperatures from 2-methyl-2-butene, sodium borohydride and borontrifluoride ethereate) and then anhydrous trimethylamine oxide. Theresulting solution and an iodine solution in tetrahydrofuran are thenadded simultaneously to an aqueous solution of sodium hydroxide to givethe 1-iodo-3-trimethylsilyloxy-trans-1-alkene (62).

(63) in turn is readily prepared by the addition of tri-n-butyl tinhydride to the acetylene (61) in the presence of bisazoisobutyronitrilefollowed by vacuum distillation at a high enough temperature (about 170°C.) to isomerize any of the cis-vinyl tin compound to the trans-vinyltin compound.

Certain of the ketones (67) of this invention are prepared as indicatedin Flowsheet H below: ##STR113## wherein n and m are as hereinabovedefined and the moiety ##STR114## represents a phenoxy group which isoptionally substituted with one or more halogen, trifluoromethyl, andlower alkoxy (C₁ to C₄) groups.

As indicated in Flowsheet H the reaction of an epoxide (64) with asubstituted or unsubstitued phenol (65) in the presence of a catalyticamount of aqueous sodium hydroxide and a phase transfer catalyst such asmethyl tricapryly ammonium chloride and the like at 70°-80° C. gives thephenoxy substituted alcohol (66) which in turn is oxidized with anoxidizing reagent such as pyridinium clorochromate in methylene chlorideto give the phenoxy substituted ketone (67). This ketone (67) is thencarried through the reactions shown in Flowsheet G above.

The other ketones (58) used in this invention are known in theliterature or can be made by procedures well known to the art [G.Lardelli, U. Lamberti, W. T. Walles and A. P. de Jonge, Rec. Trav. Chem.Pays-Bas, 86 481 (1967); Ng. Ph. Buu-Hoi, T. B. Loc and Ng Dat Xuong.,Bull. Soc. Chem. France, 174 (1958); and G. H. Posner, OrganicReactions, 19, 1 (1972)].

The preparation of the cyclopentenones of this invention containing thehydroxyketone feature (68) wherein Z is hereinabove defined and R'₃ ishydrogen or a hydroxy group can be accomplished in several ways one ofwhich involves the conversion of the corresponding cyclopentenonecontaining a carboxylate function (69) to the respective hydroxyketoneanalog (68). ##STR115## Most of the cyclopentenone carboxylic acids (69)required for the purposes of this invention have been described in theliterature or can be prepared by procedures quite analogous to thosealready described. Appropriate references are provided in the exampleswhich follow. The synthesis of certain non-reference requisitecyclopentenone carboxylic acids (69) is also described herein.

The preparation of the requisite 4-hydroxy-thiacyclo pentneones (75) isdescribed in Flowsheet I. In accordance with Flowsheet I which ishereinbelow described, treatment of 2-furyllithium (70) with aω-chloroaldehyde (71) provides the chloroalcohol (72). Treatment of thechloroalcohol (72) with ethylmercaptoacetate furnishes the hydroxyester(73) which upon hydrolysis with sodium formate/formic acid provides the3-hydroxy-cyclopentenone (74). Treatment of the cyclopentenone (74) withsulfuric acid provides the required 4-hydroxy-cyclopentenone (75).##STR116##

The conversion of the cyclopentenone carboxylic acid (69) to therespective hydroxyketone analogs (68) and the protection of thesecompounds for a conjugate addition reaction is described hereinbelow inFlowsheets J and K.

For the preparation of cyclopentenones of the type (79) wherein Z ishereinabove defined, the carboxylic acid (76) is converted to the acidchloride (77) by first forming the sodium salt with sodium hydride intetrahydrofuran (THF) and then reacting the resulting suspension withoxalyl chloride in the presence of a catalytic amount ofdimethylformamide (DMF). The resulting acid chloride (77) dissolved inether, is then added dropwise to an ether solution containing two tothree equivalents of disazomethane to produce the diazoketone (78). Thediazoketone can be hydrolized to the hydroxy ketone (79) by refluxing anetheral solution in the presence of a dilute aqueous solution ofsulfuric acid.

Alternatively, the acid chloride (77) can be heated with two equivalentsof 1,1,2-tris-trimethylsilyloxyethylene at 90°-100° for 2 to 4 hours toproduce compound (81). Compound (81) can be readily hydrolized anddecarboxylated to give the hydroxyketone (79) by treatment with dilutehydrochloric acid in tetrahydrofuran (THF).

Protection of the hydroxy ketone function of 79, suitable for aconjugate addition reaction, can be accomplished in two ways.Ketalization of 79 with ethylene glycol is accomplished by refluxing abenzene or toluene solution of 79 and ethylene glycol into a Dean-Starktrap. The resulting ketal (82) is then treated withtrimethylsilychloride (TMSCl) and imidazole in dimethylformamide (DMF)to give 83 which is suitably protected for a conjugate additionreaction.

Alternatively 79 can be protected by the reaction with a mixture of2-methoxy-1-propene (84) and 2,2-dimethoxypropane (85) in benzene in thepresence of an acid catalyst such as p-toluenesulfonic acid to give theketal 86 which is suitably protected for a conjugate addition reaction.##STR117##

The preparation of the 4-hydroxycyclopentenones of this invention (92)wherein Z is hereinabove defined is outlined in Flowsheet K below. Thereaction of the hydroxy acid (87) with at least two equivalents ofdimethyl-t-butyl silylchloride in the presence of imidazole indimethylformamide at 30°-40° C. gives the bis-dimethyl-t-butylsilatedcompound 88. The carboxylate dimethyl-t-butylsilyl group can beselectively removed by treatment with acetic acid, tetrahydrofuran andwater (4:2:1) to give the carboxylic acid (89). The acid chloride (90)is prepared by first treating the acid (89) with sodium hydride intetrahydrofuran to give the sodium salt. The resulting suspension of thesodium salt is then treated with oxalyl chloride in the presence of acatalytic amount of dimethylformamide. Alternatively the acid chloride(90) can be prepared directly by the reaction of the acid (89) or thedimethyl-t-butylsilyl ester (88) with oxalyl chloride in tetrahydrofuranin the presence of a catalytic amount of dimethylformamide at 0° C. Theslow addition of an etheral solution of the acid chloride (90) to anetheral solution of two to three equivalents of diazomethane gives thediazoketone (91) which on acid hydrolysis gives the 4-hydroxycyclopentenone (92) containing the hydroxyketone function.

Alternatively the acid chloride (90) can be heated with at least twoequivalents of 1,1,2-tris-trimethylsilylethylene at 90°-120° C. in theabsence of a solvent to give compound (93) which is readily hydrolizedand decarboxylated to give the 4-hydroxycyclopentenone (92) containingthe hydroxyketone feature. Protecting of 92 can be accomplished bytreatment with an excess of a mixture of 2-methoxy-1-propene (84) and2,2-dimethoxypropane (85) in benzene with an acid catalyst such asp-toluenesulfonic acid to give the bis-ketal (94) which is suitablyprotected for a conjugate addition reaction. ##STR118##

Another preparation of the 4-hydroxycyclopentenones of this inventionwhich contain a cis double bond in the potential α chain (109) is shownhereinbelow in Flowsheet L wherein g is as hereinabove defined. Asillustrated in Flowsheet L there are three methods available to preparethe important intermediate 98. The reaction of the ω-bromo carboxylicacid (95) with oxalyl chloride in an inert solvent such as benzene givesthe acid chloride (96). Addition of the acid chloride (96) in ether toan etheral solution of diazomethane (2 to 3 equivalents) yields thediazoketone (97) which can be hydrolized in a two phase systemconsisting of ether and dilute sulfuric acid to the hydroxyketone (98).Alternatively the acid chloride (96) can be treated with an excess of1,1,2-tris-trimethylsilyloxyethylene in the presence of a catalyticamount of stannic chloride in the absence of solvent to give compound(99) which can readily be hydrolized and decarboxylated to the desiredhydroxyketone (98) using dilute hydrochloric acid in tetrahydrofuran. Analternate method to prepare ( 98) involves the reaction of thebromoolefin (100) with aqueous n-bromosuccinimide (NBS) in the presenceof a catalytic amount of acetic acid to give a mixture of bromohydrins(101 and 102). Oxidation of the mixture of bromohydrins with anoxidizing agent such as pyridinium chlorochromate in methylene chloridegives a mixture of bromoketone (103) and bromoaldehyde (104). Refluxingthis mixture with sodium formate in methanol then gives the desiredintermediate (98). Protection of the ketone function of 98 isaccomplished using ethylene glycol in refluxing toluene using acatalytic amount of p-toluenesulfonic acid. The ketal (103) is thenreacted with dimethyl-t-butylsilylchloride and imidazole indimethylformamide to give the fully protected compound 104. Thephosphonium salt (105) is obtained by refluxing a solution of 104 andtriphenylphosphine in acetonitrile. Treatment of the phosphonium salt(105) with sodium methylsulfinylmethide in dimethylsulfoxide generates aphosphonium yield which on reaction with aldehyde 106 gives 107.Refluxing a water-dioxane solution of 107 in the presence of a phosphatebuffer (PH 5 to 6) gives the cyclopentenone (108). Treatment of 108 withchloral and triethylamine in ether gives (109) which on hydrolysis in amixture of tetrahydrofuran and dilute hydrochloric acid at 50°-70° C.then gives the desired 4-hydroxycyclopentenone (110) which can beprotected as described hereinabove in Flowsheet K.

Treatment of 109 with trimethylsilylchloride and imidazole in DMF gives111 which is also suitably protected for a conjugate addition reaction.##STR119##

The reagent 1,1,2-tris-trimethylsilyloxyethylene (80 and its use for theconversion of acid chlorides to hydroxyketone (for example 96 to 98 and90 to 92) are claimed in this invention. The reagent preparation isdescribed hereinbelow in Flowsheet M. The reaction of glycolic acid with1,1,1,3,3,3-hexamethyldisilazane and trimethylsilylchloride in pyridinegives bis-trimethylsilated glycolic acid (113). Addition of (113) to atetrahydrofuran solution of one equivalent of lithium1,1,1,3,3,3-hexamethyldisilazane amide at -78° C. generates a lithiumenolate which is trapped with trimethylsilylchloride to produce thedesired reagent (80). ##STR120##

The preparation of the prostaglandin congeners of this invention aredescribed hereinbelow in Flowheet N wherein Z is as hereinabove defined;R"₃ is hydrogen, 2-methoxypropyl-2-oxy (--OC(CH₃)₂ OCH₃) ortrimethylsilyloxy; R₃ "' is hydrogen or hydroxy; T' is the radical##STR121## wherein R₁ is as hereinabove defined. R' is selected from thegroup consisting of: ##STR122## wherein R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,R₁₃, G, p, q, t, s, m, n, y, and X are as hereinabove defined.

In accordance with Flowsheet N the vinyliodide (114) is treated witheither one equivalent of n-butyllithium or 2 equivalents oft-butyllithium at low temperature, preferably -30° to -70° C. in aninert solvent, e.g. hexane, ether or toluene to provide the transalkenyl-lithium reagent (116).

Alternatively, the vinyllithium reagent (116) can be prepared bytreatment of a vinylstannyl derivative such as (115) with n-butyllithiumat -10° to -78° C. in ether or THF.

For the preparation of the asymmetrical lithio cuprate (117) or thelike, a solution of one molar equivalent of copper (I)-1-alkyne,preferably copper (I)-1-pentyne in anhydrous hexamethylphosphoroustriamide preferably one to five molar equivalents, and anhydrous etheris added to one molar equivalent of the aforementioned vinyllithiumsolution cooled to about -78° C. After about one hour at thistemperature, a molar equivalent of the requisite cyclopentenone (120) isadded. After several hours at -78° C. to -20° C. the reaction mixture isquenched with aqueous ammonium chloride solution and the blocked product(121) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with theasymmetrical lithio cuprate (119) derived from vinyllithium (116) andcuprous thiophenoxide. A solution of vinyllithium (116) in ether at -78°C. is reacted with an equimolar amount of a reagent prepared byadmixture, in ether at a temperature of 0° C. to -78° C., of equimolaramounts of cuprous thiophenoxide and copper (I) iodidetributylphosphonium complex. After about 30 minutes at this temperature,the lithio cuprate (119) is treated with the requisite cyclopentenone(120) as described hereinabove for the conjugate addition with 1-alkynyllithio cuprate (117).

For the preparation of the symmetrical lithio cuprate (118) one molarequivalent of copper (I) iodide tributylphosphine complex, dissolved inanhydrous ether, is added at about -78° C. to two molar equivalents ofthe aforementioned vinyl lithium (116) solution in hexanes, cooled to-78° C. After about one hour at this temperature, the lithio cuprate(118) is treated with the requisite cyclopentenone (120) as describedhereinabove for the conjugate addition with the 1-alkynyl lithio cuprate(117).

The procedures for conjugate addition involving organocopper reagentsare well known in the art, see for example, C. J. Sih, et al., J.A.C.S.,97, 865 (1975).

All available evidence leads us to believe that the --CH═CH-R'₂ functionintroduced by the cuprate process occupies a position trans to the11-oxy function. Similarly, we are led to the conclusion that in theproduct (121) the two side-chains attached to C₈ and C₁₂ are trans toeach other. However, we are not certain of this configurationalrelationship in the product as it is obtained directly from the cuprateprocess. These products may have the side-chains in a trans- orcis-relationship or they may be a mixture containing both the trans- andcis-isomers. This is indicated in the nomenclature of the compoundsinvolved by the designation 8ε. In order to ensure a trans-relationshipin (121) these products can be submitted to conditions known in theliterature to equilibrate the cis-8-iso-PGE₁ to a mixture containingabout 90% of the trans product. These conditions involve treatment withpotassium acetate in aqueous methanol for 96 hours at room temperature.##STR123##

When T' is ##STR124## removal of the blocking groups from (121) to givethe prostaglandin congener (122) is accomplished by treatment of (121)with a mixture of acetic acid, tetrahydrofuran and water (4:2:1) at 25°to 55° C.

When T' is ##STR125## (121) can be partially deblocked to give the ketal(123) by treatment of (121) with 0.6 N hydrochloric acid intetrahydrofuran at room temperature for 4 to 7 hours.

In certain cases it is possible to convert the carboxylic acid functionof a prostaglandin congener into a terminal hydroxymethyl ketonefunction as shown in Flowsheet hereinbelow wherein Z, C₁₃ -C₁₄, and R isas hereinabove defined. Treatment of a prostaglandin congener (124) inwhich the hydroxy groups of the β chain are protected with a suitablegroup such as acetate or a dimethyl-t-butylsilyl ether with oxalylchloride in benzene for 2 to 5 hours furnishes the acid chloride (125).Addition of the acid chloride (125) dissolved in ether, to an ethersolution of at least three equivalents of diazomethane gives thediazoketone (126). Hydrolysis of the diazoketone using aqueous sulfuricacid and tetrahydrofuran at 55° C. gives the hydroxymethyl ketone analog(127). The acetate protecting group can be removed by refluxing withacidified methanol. The dimethyl-t-butylsilyl ether protecting group canbe removed by treatment with aqueous hydrochloric acid intetrahydrofuran at 25° to 60° C. ##STR126##

When the compounds of this invention are prepared from racemic startingcompounds two racemates are obtained. In appropriate instances theseracemates can be separated from each other by careful application of theusual chromatographic procedures. In the more difficult instances it maybe necessary to apply high pressure liquid chromatography includingrecycling techniques. [See G. Fallick, American Laboratory, 19-27(August, 1973) as well as references cited therein. Additionalinformation concerning high speed liquid chromatography and theinstruments necessary for its application is available from WatersAssociate, Inc., Maple Street, Milford, Mass].

It is also possible to prepare the compounds of this invention in theiroptically active forms by the conversion of the optically active4-hydroxycyclopent-2-en-1-one carboxylic acids (128) to the opticallyactive protected hydroxy ketone analog (129) using the methods outlinedhereinabove in Flowsheet K. ##STR127##

Conjugate addition of the vinyl cuprates to (129) followed by deblockingas described hereinabove in Flowsheet N then gives the compounds of thisinvention in their optically active forms. Although in some cases twodiastereoisomers will be formed, each optically active, they can beseparated by chromatographic procedures as described hereinabove.

The preparation of optically active 4-hydroxycyclopent-2-en-1-ones suchas (128) is described hereinbelow.

The 4-hydroxycyclopentenone racemates may be resolved into theircomponent enantiomers (130) and (131) by derivatizing the ketonefunction with a reagent having an optically active center. The resultingdiastereomeric mixture can then be separated by fractionalcrystallization, or by chromatography, or by high speed liquidchromatography involving, if necessary, recycling techniques. Among theuseful optically active ketone derivatizing reagents are1-α-aminoxy-γ-methylpentanoic acid hydrochloride [to give (132)],(R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and4-α-methylbenzyl semicarbazide. After separation of the diastereomericderivatives, reconstitution of the keto function provides the individual4-hydroxycyclopentenone enantiomers (130) and (131). A useful procedurefor the resolution of a 4-hydroxycyclopentenone racemate via an oximesuch as (132) is described in the art [R. Pappo, P. Collins and C. Jung,Tetrahedron Letters, 943 (1973)]. ##STR128##

An alternate procedure for the preparation of the4(R)-hydroxycyclopentenone enantiomers such as (130) involves as a keystep the selective microbiological or chemical reduction of trione (133)to the 4(R)-hydroxycyclopentanedione (134). A wide variety ofmicroorganisms are capable of accomplishing this asymmetric reduction,one of the most useful being Dipodascus unincleatus. This step also canbe achieved chemically by catalytic hydrogenation in the usual manner(for example, under about one atmosphere of hydrogen in methanol) usinga soluble rhodium catalyst with chiral phosphine ligands, such as(1,5-cyclooctadiene)-bis-(o-anisylcyclohexylmethylphosphine)rhodium (I)tetrafluoroborate in the presence of one equivalent of organic base,such as triethylamine.

Conversion of hydroxycyclopentanedione (134) to an enol ether or enolester, (135, E=alkyl, preferably iso-propyl; aroyl such as benzoyl; orarylsulfonyl such as 2-mesitylenesulfonyl), is accomplished bytreatment, for example, with isopropyl iodide and a base such aspotassium carbonate in refluxing acetone for from 15 to 20 hours, orwith a base such as triethylamine and 0.95 equivalents of benzoylchloride or a slight excess of 2-mesitylenesulfonyl chloride, in anon-prototropic solvent at a temperature of about -10° to -15° C.Reduction of (135) with excess sodium bis(2-methoxyethoxy)aluminumhydride in a solvent such as tetrahydrofuran or toluene at lowtemperatures, such as -60° to -78° C., followed by mild acid hydrolysis(representative conditions: aqueous dilute hydrochloric acid, pH 2.5; oroxalic acid, sodium oxalate in chloroform) at ambient temperatures from1 to 3 hours provides the 4(R)-hydroxycyclopentenone ester (136). Theester (136), can then be hydrolized to acid (130).

For a description of these procedures in the art see: C. J. Sih, et al,J.A.C.S., 95, 1676 (1973); J. B. Heather, et al., Tetrahedron Letters,2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters, 2627(1972); and R. Pappo, P. Collins, and C. Jung, Ann. N.Y. Acad. Sci.,180, 64 (1971). ##STR129##

Procedures for the preparation of the requisite cyclopentanetriones(133) are well-established in the art and generally involve thetreatment of an ω-1-oxo long chain ester (137) with methyl or ethyloxalate and a base such as sodium methoxide in methanol, followed bytreatment with dilute hydrochloric acid in aqueous methanol to effectthe dealkoxalylation of the intermediate (138). See J. Kutsube and M.Matsui, Agr. Biol. Chem., 33 1078 (1969); P. Collins, C. J. Jung and R.Pappo, Israel Journal of Chemistry, 6, 839 (1968); R. Pappo, P. Collinsand C. Jung, Ann. N.Y. Acad. Sci., 180, 64 (1971); C. J. Sih, et al.,J.A.C.S., 95, 1676 (1973) (see reference 7); and J. B. Heather, et al.,Tetrahedron Letters, 2313 (1973) for pertinent background literature.##STR130##

The intermediate keto esters (137) may be prepared by a variety ofmethods known to the art. One useful procedure is outlined below andinvolves alkylation of ethyl acetoacetate sodium salt (139) in the usualmanner with the appropriate side-chain precursor (140, X=Cl, Br, I,preferably Br or I) followed by decarbethoxylation and reesterification,all in the usual manner. ##STR131##

The side-chain precursors (140) are commercially available where Z is--(CH₂)_(p) --, and can be prepared as described in Belgian Patent786,215 (granted and opened to inspection Jan. 15, 1973).

Those precursors wherein Z is --(CH₂)_(t) --O--CH₂ -- can be prepared bythe transformation shown directly below starting with themono-tetrahydropyranyl derivative (143). Thus, (143) is converted to thelithium alcoholate by treatment with butyl lithium, the alcoholate isthen O-alkylated with ethyl bromoacetate to provide (144), which onde-O-tetrahydropyranylation, mesylation and reaction with lithiumbromide gives the required (145). (These and all the above-describedtransformations can be effected in the usual manner well-established inthe art; pertinent examples for most of the reactions can be found inthe above-cited Belgian patent 786,215). ##STR132##

It is also possible to resolve the 4-hydroxycyclopentenone racemate(146) by microbiological means. Thus, treatment of the 4-O-alkanoyl oraroyl derivatives (147, R₁₈ =aryl or alkyl) of racemate (146)(preferably the 4-O-acetyl and 4-O-propionyl derivatives) with anappropriate microorganism, preferably a Saccharomyces species e.g.,1375-143, affords preferential de-O-acylation of the 4(R)-enantiomer togive (148), which is then separated from the unreacted 4(S)--O---acylenantiomer (149) by chromatographic procedures. After separation, mildhydrolysis of the 4(S) derivative (149) provides the4(S)-hydroxycyclopentenone (150). [See N. J. Marsheck and M. Miyano,Biochima et Biphysica Acta, 316, 364 (1973) for related examples].##STR133##

It is also possible to prepare the individual 4-hydroxycyclopentenones(148) and (150) directly by selective microbial hydroxylations of thecorresponding 4-unsubstituted cyclopentenone (151). For example, withAspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of [151,Z=(CH₂)₆ ] has been reported; see S. Kurozumi, T. Tora and S. Ishimoto,Tetrahedron Letters, 4959 (1973). Other microorganisms can alsoaccomplish this hydroxylation. ##STR134##

The 9α-hydroxy compounds of this invention (154) are prepared by aconjugate addition reaction as described hereinabove in Flowsheet N. Theinitial conjugate addition product 121 (wherein Z, T', R"₃ and R are ashereinabove defined) is not deblocked but dissolved in tetrahydrofuran.An excess of lithium perhydro-9b-borophenalyhydride (PBPH) intetrahydrofuran is added at -78° C. After warming to 0° C., the reactionmixture is quenched with saturated ammonium chloride solution. Theproduct 153 is isolated and deblocked with aceticacid-tetrahydrofuran-water 4:2:1 at 40° C. in the cases where T' is##STR135## and with dilute hydrochloric acid in the cases where T' is##STR136## to give the 9α-hydroxy compounds of this invention (154). SeeFlowsheet P hereinbelow wherein Z, T', R"₃, R, R' and R'"₃ are ashereinabove defined. ##STR137##

The 9β-hydroxy compounds of this invention (156) are prepared bypreforming a conjugate addition as described hereinabove in Flowsheet N.The initial conjugate addition product 121 (wherein Z, T', R"₃ and R'are as hereinabove defined) is not deblocked but dissolved in ethanoland an excess of sodium borohydride is added. The mixture is stirred for8 hours, poured into water and the reduced products 153 and 155 areobtained. These are deblocked with acetic acid-tetrahydrofuran-water4:2:1 at 40° C. in the cases where T' is ##STR138## and with dilutehydrochloric acid in tetrahydrofuran in cases where T' is ##STR139## togive the 9α-hydroxy (154) and 9β-hydroxy (156) compounds of thisinvention which can be separated by silica gel chromatography. SeeFlowsheet Q hereinbelow wherein Z, T', R, R', R"₃, and R'"₃ are asdefined hereinabove. ##STR140##

The 1-hydroxymethyl group of the compounds of this invention can beselectively esterified by dissolving the compound (154 or 156) inpyridine and adding one equivalent of an anhydride (R₁ CO)₂ O andallowing the mixture to stand overnight to give the desired esters (157and 158). ##STR141##

The novel compounds of the present invention have potential utility ashypotensive agents, anti-ulcer agents, agents for the treatment ofgastric hypersecretion and gastric erosion, agents to provide protectionagainst the ulcerogenic and other gastric difficulties associated withthe use of various non-steroidal antiinflammatory agents (e.g.,indomethacin, aspirin, and phenylbutazone), bronchodilators,antiinflammatory agents, abortifacients, agents for the induction oflabor, agents for the induction of menses, fertility-controlling agents,oestrus regulators for use in animal husbandry with cattle and otherdomestic animals and central nervous system regulatory agents. Certainof the novel compounds of this invention possess utility asintermediates for the preparation of other of the novel compounds ofthis invention.

The novel compounds of this invention possess the pharmacologicalactivity described below as associated with the appropriateabove-described prostaglandin type.

The known PGE, PGFα, PGFβ, PGA and PGD compounds are all potent incausing multiple biological responses even at low doses. For example,PGE₁ and PGE₂ are extremely potent in causing vasodepression and smoothmuscle stimulation, and also are potent as antilipolytic agents.Moreover, for many applications, these known prostaglandins have aninconveniently short duration of biological activity. In strikingcontrast, the novel prostaglandin analogs of this invention aresubstantially more specific with regard to potency in causingprostaglandin-like biological responses, and/or having a substantially,longer duration of biological activity. Therefore, each of these novelprostaglandin analogs is surprisingly and unexpectedly more useful thanone of the corresponding above-mentioned known prostaglandins for atleast one of the pharmacological purposes indicated below for thelatter, either because it has a different and narrower spectrum ofbiological activity than the known prostaglandins, and therefore is morespecific in its activity and causes smaller and fewer undesired sideeffects than the known prostagladins, or because of its prolongedactivity, fewer and smaller doses of the novel prostaglandin analog canfrequently be used to attain the desired result.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively, orally, sublingually, intravaginally,buccally, or rectally, in addition to the usual intravenous,intramuscular, or subcutaneous injection or infusion methods indicatedabove for the uses of the known prostaglandins. These qualities areadvantageous because they facilitate maintaining uniform levels of thesecompounds in the body with fewer, shorter, or smaller doses, and makepossible self-administration by the patient.

PGFα, and PGFβ, compounds, and their esters and pharmacologicallyacceptable salts, are extremely potent in causing various biologicalresponses. For that reason, these compounds are useful forpharmacological purposes. See, for example, Bergstron, et al.,Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few ofthose biological responses are systemic arterial blood pressure loweringin the case of the PGE compounds as measured, for example, inanesthetized (phenobarbital sodium) pentolinium-treated rats withindwelling aortic and right hear cannulas; pressor activity, similarlymeasured, for the PGF compounds; stimulation of both muscle as shown,for example, by tests on strips of guinea pig lieum, rabbit duodenum, orgerbil colon: potentiation of other smooth muscle stimulants;antilipolytic activity as shown by antagonism of epinephrine-inducedmobilization of free fatty acids or inhibition of the spontaneousrelease of glycerol from isolated rat fat pads.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdisease and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, are useful in mammals, including man, asnasal decogestants. For this purpose, the compounds are used in a doserange of about 10 mg to about 10 mg. per ml. of a pharmacologicallysuitable liquid vehicle or as an aerosol spray, both for topicalapplication.

The PGEβ compounds are useful as hypotensive agents to reduce bloodpressure in mammals including man. For this purpose, the compounds areadministered by intravenous infusion at the rate of about 0.01 mg. toabout 40 mg. per kg. of body weight per minute, or in a single ormultiple doses of about 25 mg. to 2500 mg. per kg of body weight totalper day.

The PGFα and PGFβ compounds are useful in place of oxytocin to inducelabor in pregnant female animals, including man, cows, sheep, pigs, ator near term or in pregnant animals with intrauterine death of the fetusfrom about 20 weeks to term. For this purpose, the compound is infusedintraveneously at a dose of 0.01 mg. to 50 mg. per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks postmature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started.

The PGFα and PGFβ compounds are useful for controlling the reproductivecycle in ovulating female mammals, including humans and other animals.For that purpose, PFG₂α', for example, is administered systemically at adose level in the range of 0.01 mg to about 20 mg. per kg. of bodyweight, advantageously during a span of time starting approximately atthe time of ovulation and ending approximately at the time of menses orjust prior to menses. Additionally, expulsion of an embryo or fetus isaccomplished by similar administration of the compound during the firstthird or the second third of the normal mammalian gestation period.Accordingly, they are useful as abortifacients. They are also useful forinduction of menses during approximately the first two weeks of a missedmenstrual period and accordingly, are useful as contraceptiveanti-fertility agents.

The novel compounds of this invention induce the biological responsesdescribed hereinabove as associated with its particular prostaglandintype. These novel compounds are accordingly used for the above-describedcorresponding purposes.

The novel PFGβ compounds of this invention are also useful asbronchodilators for the treatment of asthma and chronic bronchitis. Assuch, they may be conveniently administered by inhalation of aerosolsprays prepared in a dose range of about 10 mg. to about 10 mg./ml. of apharmacologically suitable liquid vehicle. Relative to the naturalprostaglandins, the PGE compounds in particular have the significantadvantage of inducing prolonged effects.

The invention will be described in greater detail in conjunction withthe following specific examples.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Preparation of ethyl2,2-trimethylenehexanoate

To a stirred solution of 27.6 g of freshly distilledN-isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran cooled to-78° C. is added at a fast rate 96 ml of 2.04 M n-butyllithium inhexane. To the resulting solution is added dropwise 25 g of ethylcyclobutanecarboxylate. After 30 minutes the resulting solution isallowed to warm to ambient temperature, is transferred to a droppingfunnel under nitrogen and is added dropwise over a period of 11/4 hoursto a solution of 54 g of n-butyl iodide in 100 ml of drydimethylsulfoxide maintaining the temperature at 16°-20° C. Stirring iscontinued for an additional 30 minutes. The separated salts are removedby filtration, the mother liquor is taken to a small volume and theresulting oil is diluted with hexanes. This solution is washed with 2%hydrochloric acid, saturated sodium chloride solution, and dried withanhydrous magnesium sulfate. The solvent is removed and the residual oilis distilled to give 14.6 g (41%) of product, bp 84°-87° C. (10 mm).

EXAMPLE 2 Preparation of ethyl 2,2-tetramethylenehexanoate

In the manner described in Example 1, treatment of the lithium salt ofethyl cyclopentanecarboxylate with n-butyl iodide furnishes the subjectproduct.

EXAMPLE 3 Preparation of 2,2-trimethylenehexan-2-ol

To a stirred solution of 20 g of ethyl 2,2-trimethylenehexanoate(Example 1) in 100 ml of dry toluene, in an argon atmosphere and cooledin an ice bath, is added dropwise 250 ml (2 molar equivalents) of 0.89 Mdiisobutlaluminum hydride in toluene. The resulting solution is stirredat ambient temperature for 2 hours and then poured into excess iced 5%hydrochloric acid. The organic phase is separated and washed with 5%hydrochloric acid, saturated sodium chloride solution, dried withanhydrous magnesium sulfate and taken to dryness to give 14.8 g (96%) ofoil; bp 92°-93° C. (10 mm).

EXAMPLE 4 Preparation of 2,2-tetramethylenehexan-1-ol

In the manner described in Example 3, treatment of ethyl2,2-tetramethylenehexanoate (Example 2) with 0.89 molardiisobutylaluminum hydride furnishes the subject product.

EXAMPLE 5 Preparation of 2,2-trimethylenehexaldehyde

Chromium trioxide (61.5 g), dried in a vacuum desicator over phosphorouspentoxide, is added to an ice cold solution of 97 g of dry pyridine inone liter of dry methylene chloride. The deep red suspension is stirredfor 15 minutes at 0° C. and then for 45 minutes at ambient temperature.A solution of 14.5 g of 2,2-trimethylenehexanol-1 (Example 3) in 55 mlof methylene chloride is added all at once to the suspension. A blacktarry deposit is formed immediately. After stirring at ambienttemperature for 15 minutes the solution is decanted from the tarrydeposit which is then triturated four times with small portions ofmethylene chloride. The combined extracts are washed twice with ice cold5% sodium hydroxide, ice cold 5% hydrochloric acid and finally withsaturated sodium chloride solution, dried with magnesium sulfate andtaken to dryness. Distillation gives 12.9 g of product; bp 69° C. (11mm).

EXAMPLE 6 Preparation of 2,2-tetramethylenehexaldehyde

Oxidation of 2,2-tetramethylenehexan-1-ol (Example 4) with chromiumtrioxide-pyridine complex in the manner described in Example 5 furnishesthe subject product.

EXAMPLE 7 Preparation of 4,4-trimethylene-1-octyn-3-ol

To a solution of lithium acetylide-ethylenediamine complex (9.4 g) in 90ml of dry dimethylsulfoxide, cooled in an ice bath, is added 12.94 g of2,2-trimethylenehexaldehyde (Example 5) in 10 ml of dimethylsulfoxidedropwise, at such a rate that the temperature is maintained at 20°-25°C. The solution is stirred at ambient temperature for 12 hours and thenpoured into a mixture of ice cold 2% hydrochloric acid and ether. Theether layer is separated and the aqueous phase is extracted with ether.The combined ether extracts are washed with saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and taken to dryness.Distillation provides 13.53 g of product; bp 108°-109° C. (13 mm).

EXAMPLE 8 Preparation of 4,4-tetramethylene-l-octyn-3-ol

Treatment of 2,2-tetramethylenehexaldehyde (Example 6) with lithiumacetylide-ethylenediamine complex in dimethylsulfoxide in the mannerdescribed in Example 4 is productive of the subject compound.

EXAMPLE 9 Preparation of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a stirred solution of 5.3 g of 4,4-trimethylene-1-octyn-3-ol (Example7) and 5.42 g of imidazole in 32 ml of dry dimethylformamide, cooled inan ice bath under argon atmosphere is added 4.35 g ofchlorotrimethylsilane. After stirring at 0° C. for 15 minutes, thesolution is stirred at ambient temperature for 18 hours and then pouredinto 200 ml of hexanes. The solution is washed twice with ice coldwater, saturated sodium chloride solution, dried with anhydrousmagnesium sulfate and taken to dryness. Distillation furnishes washedtwice with ice cold water, saturated sodium chloride solution, driedwith anhydrous magnesium sulfate and taken to dryness. Distillationfurnishes 6.02 g (80%) of colorless oil; bp 110°-112° C. (14 mm).

EXAMPLE 10 Preparation of4,4-tetramethylene-3-trimethylsilyloxy-1-octyne

Treatment of 4,4-tetramethylene-1-octyn-3-ol (Example 8) withchlorotrimethylsilane in dimethylformamide containing imidazole asdescribed in Example 5 furnishes the subject product.

EXAMPLE 11 Preparation of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a solution of 25 g of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne(Example 9), stirred under argon atmosphere at -78° C., is addeddropwise 93 ml of 2.3 M n-butyllithium in hexane at a rate to maintainthe temperature below -40° C. After stirring for 40 minutes, a solutionof iodine is allowed to warm to ambient temperature and 10% aqueoussodium thiosulfate solution is added until the purple color is removed.The organic phase is washed with dilute aqueous sodium thiosulfatesolution, saturated sodium chloride solution, dried with anhydroussodium sulfate and taken to dryness to afford the subject product as anoil.

EXAMPLE 12 Preparation of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-cis-octene

To a solution of 30 g of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 10) in 100ml of methanol, under argon atmosphere is added 54 g of potassiumazodicarboxylate [J. Thiele, Annalen der Chemie, 271, 127 (1892)] Tothis solution is added dropwise 45 ml of acetic acid over a period ofabout 2 hours. The solids are removed by filtration and the motherliquor is reduced to a small volume; diluted with water and extractedwith ether. The ether is evaporated and the residual oil is stirred with250 ml of 1 M sodium bicarbonate solution. The solution is extractedseveral times with ether and the combined extracts are washed withsaturated sodium chloride solution, dried with anhydrous sodium sulfateand taken to dryness to furnishe the subject product as an oil.

EXAMPLE 13 Preparation of1-iodo-4,4-trimethylene-3-trimethylsilyloxy--1-trans-octene

To a mixture of 4.76 g of sodiumborohydride and 23.6 g of2-methyl-2-methyl-2-butene in 220 ml of dry tetrahydrofuran at -5° C. isadded dropwise 23.8 g of freshly distilled borontrifluoride etherate.The resulting mixture is stirred at -5° C. to -0° C. for 2 hours and toit is added dropwise a solution of 20 g of4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 12) in 20 ml ofdry tetrahydrofuran. The resulting mixture is stirred at ambienttemperature for 21/2 hours. The mixture is then cooled to -5° C. andthere is added 44 g of trimethylene oxide portionwise over a period of20 minutes, maintaining the temperature at 15°-20° C. The mixture isstirred at ambient temperature for 2 hours and then pouredsimultaneously, with a solution of 119 g of iodine in 290 ml oftetrahydrofuran, into 1490 ml of 15% aqueous sodium hydroxide solution.After stirring for 30 minutes the organic phase is separated and theaqueous phase is extracted with ether. The combined organic phase iswashed with 5% aqueous sodium thiosulfate solution, saturated sodiumchloride solution, dried with anhydrous magnesium sulfate and taken todryness to give 27 g of oily material. Chromatography on 135 g offlorisil and eluting with 500 ml of hexanes furnishes 24 g of oilyproduct which is shown to be contaminated with starting material andiodoform by infrared and thin layer chromatography. The material ispurified by removing the trimethylsilyl group in the following manner.The crude product is dissolved in 350 ml of aceticacid-tetrahydrofuran-water (4:2:1) by stirring at ambient temperaturefor 5 minutes. The solvent is removed under reduced pressure and theresidual oil containing mainly1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octen is applied to a 2"(flat) dry column containing 1200 g of Woelm silica gel. The column isdeveloped with benzene, cut into one-inch segments and each segment iseluted with chloroform. Combination of the appropriate fractions affords300 mg of iodomethane, 2.8 g of 4,4-trimethylene-1-octyne-3-ol, and 11.6g of 1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene. Silylation ofthis material in the manner described above followed by distillation ofthe residual oil furnishes 13 g of pure product; bp 83°-84° C. (0.2 mm).

EXAMPLE 14 Preparation of1-iodo-4,4-tetramethylene-3-trimethylsilyloxy-1-trans-octene

Treatment of 4,4-tetramethylene-3-trimethylsilyloxy-1-octene (Example10) in the manner described in Example 13 furnishes the subject product.

EXAMPLES 15-20

Treatment of the lithium salt of ethyl cyclobutanecarboxylate with thealkyl halides listed in Table 1 below by the procedure described inExample 1 furnishes the 2,2-trimethylene esters of the table.

                  TABLE 1                                                         ______________________________________                                        Ex-                                                                           am-                                                                           ple  Alkyl Halides                                                                            Product 2,2-Trimethylene esters                               ______________________________________                                        15   propyl iodide                                                                            ethyl 2,2-trimethylenepentanoate                              16   amyl iodide                                                                              ethyl 2,2-trimethyleneheptanoate                              17   hexyl iodide                                                                             ethyl 2,2-trimethyleneoctanoate                               18   benzyl iodide                                                                            ethyl 2,2-trimethylene-3-phenylpropionate                     19   2-cyclo-   ethyl 2,2-trimethylene-4-cyclopentylbutyrate                       pentyl-1-                                                                     ethyl bromide                                                            20   1-chloro-2-                                                                              ethyl 2,2-trimethylene-4-hexynoate                                 butyne                                                                   ______________________________________                                    

EXAMPLES 21-27

Reduction of the various esters listed in Table 2 below withdiisobutylaluminum hydride all in the manner described in Example 3above is productive of the alcohols of the table.

                  TABLE 2                                                         ______________________________________                                        Exam- Starting Esters                                                         ple   of Example  Product Alcohols                                            ______________________________________                                        21    15          2,2-trimethylenepentan-1-ol                                 22    16          2,2-trimethyleneheptan-1-ol                                 23    17          2,2-trimethyleneoctan-1-ol                                  24    18          2,2-trimethylene-3-phenylpropan-1-ol                        25    19          2,2-trimethylene-4-cyclopentylbutan-1-ol                    26    20          2,2-trimethylene-4-hexyn-1-ol                               27    55          2,2-trimethylene-4-cis-hexen-1-ol                           ______________________________________                                    

EXAMPLES 28-34

Oxidation of the alcohols listed in Table 3 below with chromiumtrioxide-pyridine complex by the procedure described in Example 5 abovefurnishes the corresponding aldehydes of the table.

                  TABLE 3                                                         ______________________________________                                              Starting                                                                Exam- Alcohols                                                                ple   of Example                                                                              Product 2,2-Trimethylenealdehydes                             ______________________________________                                        28    21        2,2-trimethylenevaleraldehyde                                 29    22        2,2-trimethyleneheptaldehye                                   30    23        2,2-trimethyleneoctaldehyde                                   31    24        2,2-trimethylene-3-phenylpropionylaldehyde                    32    25        2,2-trimethylene-4-cyclopentylbutyraldehyde                   33    26        2,2-trimethylenehex-4-yn-1-al                                 34    27        2,2-trimethylene-4-cis-hexene-1-al                            ______________________________________                                    

EXAMPLES 35-41

Treatment of the various aldehydes listed below in Table 4 with lithiumacetylide-ethylenediamine complex in the manner described in Example 7furnishes the hydroxyacetylenes of the table.

                  TABLE 4                                                         ______________________________________                                              Starting                                                                Exam- Aldehydes                                                               ple   of Example                                                                              Product Hydroxyacetylenes                                     ______________________________________                                        35    28        4,4-trimethylene-1-heptyn-3-ol                                36    29        4,4-trimethylene-1-nonyn-3-ol                                 37    30        4,4-trimethylene-1-decyn-3-ol                                 38    31        4,4-trimethylene-5-phenyl-1-pentyn-3-ol                       39    32        4,4-trimethylene-6-cyclopentyl-1-hexyn-3-ol                   40    33        4,4-trimethylene-1,6-octadiyn-3-ol                            41    34        4,4-trimethylene-4-cis-hexene-3-ol                            ______________________________________                                    

EXAMPLES 42-48

Treatment of the various alcohols listed below in Table 5 withchlorotrimethylsilane in the manner described in Example 9 furnishes thecorresponding trimethylsilyloxy acetylenes of the table.

                  TABLE 5                                                         ______________________________________                                        Ex-  Starting                                                                 am-  Alcohols                                                                 ple  of Example                                                                              Product Trimethylsilyloxyacetylenes                            ______________________________________                                        42   35        4,4-trimethylene-3-trimethylsilyloxy-1-heptyne                 43   36        4,4-trimethylene-3-trimethylsilyloxy-1-nonyne                  44   37        4,4-trimethylene-3-trimethylsilyloxy-1-decyne                  45   38        4,4-trimethylene-3-trimethylsilyloxy-5-phenyl-                                1-pentyne                                                      46   39        4,4-trimethylene-3-trimethylsilyloxy-6-cyclo-                                 pentyl-1-hexyne                                                47   40        4,4-trimethylene-3-trimethylsilyloxy-1,6-                                     octadiyne                                                      48   41        4,4-trimethylene-3-trimethylsilyloxy-4-cis-                                   octene-1-yne                                                   ______________________________________                                    

EXAMPLES 49-54

In the manner described in Example 13 treatment of the variousacetylenes of Table 6 below with disiamylborane, made in situ fromsodium borohydride and 2-methyl-2-butene, followed by oxidation of theso formed organoborane with trimethylamine oxide followed by treatmentof this product with iodine and sodium hydroxide furnishes thetrimethylsilyliodovinylcarbinols of the table.

                  TABLE 6                                                         ______________________________________                                        Ex-  Starting                                                                 am-  Acetylenes                                                               ple  of Example                                                                              Product Trimethylsilylvinylcarbinols                           ______________________________________                                        49   42        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-heptene                                                  50   43        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-nonene                                                   51   44        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-decene                                                   52   45        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-5-                                phenyl-1-trans-pentene                                         53   46        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-6-                                cyclopentyl-1-trans-hexene                                     54   47        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-octen-6-yne                                              ______________________________________                                    

EXAMPLE 55 Preparation of ethyl 2,2-trimethylene-4-cis-hexenoate

A solution of 5 g of ethyl 2,2-trimethylene-4-hexynoate (Example 20) in40 ml of dry pyridine is hydrogenated in a Parr apparatus using 600 mgof 5% palladium on barium sulfate. After one hour when hydrogen uptakeis complete, the solution is filtered through celite and the motherliquor is taken to dryness to furnish 4 g of product as a oil.

EXAMPLE 56 Preparation of 3-tetrahydropyranyloxy-1-propyne

To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooledto 0° C. in a ice bath, is added a solution of 20 mg ofpara-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. Thereaction mixture is stirred at 0° C. for one-half hour, and at ambienttemperature for one hour. It is then poured into 200 ml of a 5% solutionof sodium bicarbonate, the organic phase is separated, the aqueous phaseextracted with 100 ml of methylene chloride, the combined organic phaseswashed with 100 ml of a solution of brine, dried over sodium sulfate,and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crudeproduct, which is purified by fractional distillation, bp 71°-73° C. (14mm) to yield 250 g (89%) of a liquid.

EXAMPLE 57 Preparation of3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne

To a stirred -20° C. solution of 125 g (0.89 mol.) of3-tetrahydropyranyloxy-1-propyne (Example 56) in 450 ml of ether, undera nitrogen atmosphere, is added dropwise, over one hour, a solution of45 ml (0.89 mol.) of 2.0 N n-butyllithium in hexane. After 150 ml of dryether is added and the mixture stirred at -20° C. for 30 minutes, asolution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of etheris added dropwise. Stirring is continued for 30 minutes at -20° C. andat ambient temperature for 18 hours. The reaction mixture is againcooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml ofether is added dropwise, followed by 90 ml of water. It is then dilutedwith 500 ml of water, and extracted 3 times with 300 ml of 5% sodiumbicarbonate solution. The organic phase is separated, washed with 500 mlof a saturated brine solution, dried over sodium sulfate, and evaporatedat 40° C. under vacuum (12 mm.). The crude product is fractionallydistilled, bp 120°-125° C. (18 mm.), to yield 120 g of an oil.

EXAMPLE 58 Preparation ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne

To a stirred -78° C. solution of 62 ml (124 mmol.) of a 2.0 M solutionof n-butyllithium in hexane and 50 ml of dry tetrahydrofuran, under anitrogen atmosphere is added dropwise, a solution of 24 g (113 mmol.) of3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne (Example 57) in 35 mlof tetrahydrofuran. This red solution is stirred one hour at -78° C.,then a freshly prepared solution of zinc iodide (135 mmol.) in 125 ml oftetrahydrofuran [F. Mercier, R. Epstein, and S. Holand, Bull. Soc. Chim.France, 2, 690 (1972)] is added dropwise at -78° C., until the mixtureturns yellow. After stirring an additional hour at -78° C., a solutionof 21 g (250 mmol.) of n-valeraldehyde in 35 ml of tetrahydrofuran isadded dropwise and the reaction mixture stirred for one hour at -78° C.and 18 hours at ambient temperature. It is then cooled to 0° C. and asolution of 12 ml of acetic acid in 65 ml of ether is added dropwise,followed by 75 ml of ice-water. The phases are separated and the aqueousphase is extracted twice with ether. The combined organic phases arewashed 3 times with saturated sodium bicarbonate solution, until thelast wash is basic, then with a saturated brine solution, dried oversodium sulfate, and evaporated to give 40 g of yellow oil. The crudeproduct may be purified on a 4"×40" dry column of alumina, and elutedwith chloroform. I.R.: neat; 3550 (OH), 2200 (C.tbd.C), 840, 750 [(CH₃)₃Si], cm⁻¹.

EXAMPLE 59 Preparation ofd,1-erythro-3,4-dihydroxy-1-trimethylsilyl-1-octyne

A solution of 19.6 g (0.066 mol) ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne(Example 58) in 55.5 ml of ethanol, 22.2 ml of acetic acid, and 22.2 mlof water is heated at reflux for 3 hours. The cooled mixture is taken todryness and evaporated twice with benzene. The residue is taken up inhexane, washed 3 times with saturated potassium bicarbonate solution,dried with magnesium sulfate, and evaporated to give 17.0 g of crudeproduct IR: neat, 3500-3400, broad (two OH).

EXAMPLE 60 Preparation ofd,1-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne

To a stirred solution of 17.0 g (79.5 mmol.) of cruded,1-erythro-15,16-dihydroxy-1-trimethylsilyl-1-octyne (Example 59) is33.6 ml of 2,2-dimethoxy propane at 0° C., is added 0.05 ml of 60%perchloric acid. After 30 minutes at ambient temperature, the mixture isshaken with 50 ml of hexane and 25 ml of saturated sodium bicarbonatesolution. The hexane phase is separated, dried with magnesium sulfate,and evaporated to give 19.0 g of crude product.

EXAMPLE 61 Preparation of d,1-erythro-3,4-isopropylidenedioxy-1-octyne

A mixture of 19.0g (75.0 mmol.) of cruded,1-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne (Example60) with 95 ml of methanol and 3.0 g of potassium carbonate is refluxedfor one hour. The mixture is cooled and evaporated at 50° C. (13 mm),taken up in 250 ml of benzene, and washed with 100 ml of water. Thewater is saturated with salt, the organic phase separated, dried withmagnesium sulfate, and evaporated to give 12 g crude product. Fractionaldistallation yields 7.0 g of the subject compound as a colorless oil, bp103°-106° C. (13 mm).

IR: neat; 3300 sharp (H-C.tbd.C), 2100, (C.tbd.C), 780 (erythroconfiguration) cm⁻¹.

nmr: δ _(TMS) ³ CDCl.sbsp.3 ; 4.75 (dd., 1, C.tbd.C-CH-CH, J=2Hz,J=5Hz), 4.10 (m, 1, C.tbd.C--CH--CH--CH₂, 2.5 (d, 1, H--C C--CH),1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂ CH₃).

EXAMPLE 62 Preparation ofd,1-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

To a stirred 0° C. slurry of 0.852 g (0.023 mol.) of sodium borohydrideand 4.21 g (0.060 mol.) of 2-methyl-2-butene in 40 ml of drytetrahydrofuran, under an argon atmosphere, is added dropwise 4.26 g(0.030 mol.) of boron trifluoride etherate complex. A solution of 2.73 g(0.015 mol.) of d,1-erythro-3,4-isopropylidenedioxy-1-octyne (Example61) in 5 ml of tetrahydrofura is added dropwise, the ice bath removed,and the mixture allowed to stir at ambient temperature of two hours. Itis then cooled again to 0° C., and 2.88 g (0.105 mol.) of drytrimethylamine oxide is added in portions over 30 minutes. Afterstirring 3 hours at room temperature, this mixture is pouredsimultaneously with a 0° C. solution of 2.13 g of iodine in 53 ml oftetrahydrofuran into 766 ml of a 0° C. 15% solution of sodium hydroxidein water and the whole stirred vigorously at 0° C. for 45 minutes. Theorganic phase is separated, the aqueous phase is extracted twice withether, the combined organic phases are washed with a 5% solution ofsodium thiosulfate, dried with magnesium sulfate, and evaporated. Thecrude product is chromatographed on a 2" by 40" dry column of silicagel, by eluting with chloroform, to yield 1.2 g (25%) of a yellow oil.IR: neat; 1599 sharp, 945 ##STR142## cm⁻¹ 1.

EXAMPLE 63 Preparation ofd,1-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A solution of 3.0 g (13.2 mmol.) ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyneis heated at 100° C. for 15 hours with 3 ml of acetic anhydride and 10ml of pyridien. The mixture is evaporated to dryness, dissolved inether, washed with sodium bicarbonate solution and water. The organicphase is dried over magnesium sulfate and evaporated to give 2.5 g ofthe subject compound as an oil IR: neat; 2200 (C C), 1730 (C=O), 830,760 [(CH₃)₃ Si], cm⁻¹.

EXAMPLE 64 Preparation ofd,1-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

In the manner of Example 59, 2.5 g (7.4 mmol.) ofd,1-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne(Example 63) in a solution of ethanol, acetic acid, and water is heatedat 100° C. for 3 hours. After workup, the crude product ischromatographed on a 7/8"×22" dry column of silica gel, and eluted withchloroform to give 1.0 g of a yellow oil.

IR: neat; 3500 (OH), 1730 (C═O), cm⁻¹.

EXAMPLE 65 Preparation ofd,1-erythro-3-paratoluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

To a solution of 7.5 g (41.0 mmol.) ofd,1-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 64)in 41 ml of dry pyridine is added 11.0 g (58 mmol.) ofparatoluenesulfonyl chloride and the resulting solution is stirred at25° C. for 15 hours. The mixture is then warmed at 40° C. for one hour,and after cooling, partitioned between 500 ml of diethyl ether and 100of 1.0 N hydrochloric acid. The organic phase is washed three times with100 ml of 1.0 N hydrochloric acid, once with dilute sodium bicarbonatesolution, dried over magnesium sulfate, and evaporated under reducedpressure to give an oil. The crude product is purified on a 2"×24" drycolumn of silica gel, and eluted with chloroform to yield a yellow oil.

IR: neat, 1730 (C═O), 1595 (aromatic) cm⁻¹.

EXAMPLE 66 Preparation ofd,1-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A mixture of 15.5 g (39.0 mmol.) ofd,1-erythro-3-para-toluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne(Example 65), 5.0 g of calcium carbonate, 25 ml of water and 250 ml oftetrahydrofuran is refluxed with stirring for 4 days. The mixture iscooled, 100 ml of water added and the organic phase separated. Theaqueous phase is extracted with ether, the combined organic phases driedwith magnesium sulfate, and evaporated. The crude product ischromatographed on a 3"×30" dry column of silica gel, and eluted withchloroform to give 7.0 g of an oil.

IR: neat; 3500, (OH), cm⁻¹.

EXAMPLE 67 Preparation of d,1-threo-3,4-dihydroxy-1-octyne

A solution of 7.0 g (28 mmol.) ofd,1-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 66)in 50 ml of methanol is stirred at room temperature for 24 hours with asolution of 6.3 g (112 mmol.) of potassium hydroxide in 50 ml of water.The mixture is extracted twice with hexane, washed with 0.5Mhydrochloric acid, brine, and dried with magnesium sulfate. Afterevaporation, the subject compound is obtained as a yellow oil.

IR: neat, 2500 broad (2-OH), cm⁻¹.

EXAMPLE 68 Preparation of d,1-threo-3,4-isopropylidenedioxy-1-octyne

In the manner of Example 60, treatment of a solution ofd,1-threo-3,4-dihydroxy-1-octyne (Example 67) in dimethoxypropane with60% perchloric acid, and fractional distillation (12 mm) is productiveof the subject compound as a colorless oil, containing 15% ofd,1-erythro-3,4-isopropylidenedioxy-1-octyne (Example 60), as animpurity.

IR: neat; 810 (threo configuration).

nmr: δ _(TMS) ^(CDCl).sbsp.3 ; 4.2 (dd, 1, --C.tbd.C--CH--, J's -2H_(z), 6H_(z)), 4.1-3.9 (m, 1, --C.tbd.C--CH--CH--CH₂ --), 2.5 (d, 1,H--C.tbd.C--, J=2H_(z)), 1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂--CH₃).

EXAMPLE 69 Preparation ofd,1-threo-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

In the manner of Example 62,d,1-threo-3,4-isopropylidenedioxy-trans-1-octyne (Example 68) is treatedsuccessively with disiamylborane, trimethylamine oxide, iodine, andsodium hydroxide to give the subject compound.

EXAMPLE 70 Preparation ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne

Alakline hydrolysis ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne(Example 58) by the procedure of Example 61 is productive of the subjectcompound.

EXAMPLE 71 Preparation ofd,1-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne

To a stirred slurry of 6.0 g (150 mmol.) of a 60% oil dispersion ofsodium hydride and 96 g of iodomethane, under an argon atmosphere, isadded 700 ml of dry tetrahydrofuran. The stirred mixture is cooled to-20° C. and a solution of 30 g (133 mmol.) ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-oxtyne (Example 70), isadded dropwise, followed by 0.1 ml of methanol. The mixture is stirredat ambient temperature for 24 hours, 10 ml of methanol is added, andevaporated. The residue is taken up in ether, washed 3 times with water,dried over magnesium sulfate, and evaporated. The crude product ispurified by fractional distillation to yield 16.3 g of a colorless oil,bp 137°-140° C. (12 mm).

EXAMPLE 72 Preparation ofd,1-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octen

In the manner of Example 62, 1.20 g (5.0 mmol.) ofd,1-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne (Example 71) istreated successively with disiamylborane, trimethylamine oxide, iodine,and sodium hydroxide. Chromatography on a 2"×36" dry column of silicagel and elution with chloroform is productive of 0.80 g (40%) of thesubject compound as an oil.

nmr: δ _(TMS) ^(CDCl).sbsp.3 ; 7.9-6.1 (m,2, HC═CH), 4.9-4.6 (2m, 2,c═C--CH, O--CH--O), 4.3-4.0 (m, 1, c═c--CH--CH--CH₂), 3.9-3.0 (m, 6, CH₂--O--CH, OCH₃), 1.8-1.2 (m, 12H, alkyl), 0.9 (m, 3, --CH₃).

EXAMPLE 73 Preparation ofd,1-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene

A solution of 3.10 g (8.24 mmol.) ofd,1-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octene(Example 72) in 60 ml of acetic acid, 30 ml of tetrahydrofuran, and 15ml of water is stirred at ambient temperature for 18 hours. It is thenevaporated at 70° C. under high vacuum (1.0 mm), and three times with 40ml of toluene to give the crude product as an oil.

EXAMPLE 74 Preparation ofd,1-erythro-3-trimethylsilyloxy-4-methoxy-1-iodo-trans-1-octene

To a stirred solution of 3.0 g (10.2 mmol.) ofd,1-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene (Example 73) in11.0 ml of dry dimethylformamide and 1.90 g (28.0 mmol.) of imidazolecooled to 0° C. is added, dropwise, 1.35 g (12.5 mmol.) oftrimethylsilyl chloride. The reaction mixture is stirred a further 4hours at room temperature. It is then poured into a mixture of 100 ml ofhexane and 25 ml of water, the organic phase is separated, washed twicewith water once with a solution of saturated sodium chloride, dried overmagnesium sulfate, and evaporated. The crude product is purified byfractional distillation to yield 2.0 g of a colorless oil, bp 82°-83° C.(0.3 mm). IR: neat; 1602 sharp ##STR143## 840, 750 broad [(CH₃)₃ Si-],cm⁻¹.

EXAMPLE 75 Preparation ofd,1-erythro-1-iodo-3,4-dihydroxy-trans-1-octene

A solution of 1.40 g (4.50 mmol.) ofd,1-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene (Example 62)in 30 ml of acetic acid, 10 ml of tetrahydrofuran and 10 ml of water isstirred and heated at 50° C. for five hours. It is then evaporated at40° C. under high vacuum (1.0 mm), and twice more with 50 ml of benzene.Crystallization from 10 ml of chloroform at 0° C. is productive of 700mg of the white crystalline subject product.

EXAMPLE 76 Preparation ofd,1-erythro-1-iodo-3,4-bis-trimethylsilyloxy-trans-1-octene

To a stirred solution of 700 mg (2.40 mmol.) ofd,1-erythro-1-iodo-3,4-dihydroxy-trans-1-octene (Example 75) and 800 mg(12.0 mmol.) of imidazole, in 10 ml of dry dimethylformamide at 0° C. isadded dropwise 1.20 g (11.0 mmol.) of trimethylchlorosilane. The icebath is removed, and the mixture is stirred and heated at 50° C. forfive hours. It is then cooled, shaken with 50 ml of hexane and 50 ml ofwater, the organic layer separated and wshed with 15 ml of 0.5Mhydrochloric acid, 15 ml of a saturated solution of sodium bicarbonate,dried with magnesium sulfate, and evaporated. This crude product isfractionally distilled, bp 90°-92° C. (0.40 mm) to yield 250 mg of acolorless oil.

EXAMPLE 77 Preparation ofd,1-erythro-3-trimethylsilyloxy-4-ethoxy-1-iodo-trans-1-octene

Following the procedure of Example 71, ethylation using iodoethane ofd,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne for a period of 22hours is productive of the correspondingd,1-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-octyne. This intermediateis converted tod,1-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-iodo-trans-1-octene whentreated successively with disiamylborane, trimethylamine oxide iodine,and sodium hydroxide solution after the procedure of Example 72. Acidhydrolysis by the method of Example 18 tod,1-erythro-3-hydroxy-4-ethoxy-1-iodo-trans-1-octene, followed bytreatment with chlorotrimethylsilane and imidazole in dimethylformamideusing the procedure of Example 74, and subsequent distillation, isproductive of the subject compound.

EXAMPLES 78-82

By the method of Example 58 reaction of1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne with n-butyllithiumand subsequent treatment with the aldehydes listed in Table 7, below,provides thed,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynesof the table.

                                      TABLE 7                                     __________________________________________________________________________                   Product d,l-erythro-3-tetrahydropyranyloxy-                    Example                                                                            Starting Aldehyde                                                                       4-hydroxy-1-trimethylsilyl-1-alkyne                            __________________________________________________________________________    78   n-butanal d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-1-heptyne                                              79   n-hexanal d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-1-nonyne                                               80   n-heptanal                                                                              d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-1-decyne                                               81   4-methyl-n-pentanal                                                                     d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-7-methyl-1-octyne                                      82   2-trans-n-pentenal                                                                      d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-5-trans-en                                             __________________________________________________________________________

EXAMPLES 83-87

Hydrolysis of the 3-tetrahydropyranyloxy group of thed,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkyneslisted in Table 8 below by the method described in Example 59, followedby conversion of the resultingd,1-erythro-1-trimethylsilyl-3,4-dihydroxy-1-alkyne to the correspondingd,1-erythro-1-trimethylsilyl-3,4-isopropylidenedioxy-1-alkyne bytreatment with dimethoxypropane in the presence of perchloric acid bythe method described in Example 60, followed by desilylation to thecorresponding d,1-erythro-3,4-isopropylidenedioxy-1-alkyne by theprocedure of Example 61 followed by treatment with disiamylborane,trimethylamine oxide, iodine, and sodium hydroxide solution by themethod described in Example 62 provides the productd,1-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 8,below.

                                      TABLE 8                                     __________________________________________________________________________         Starting d,l-erythro-1-trimethyl-                                             silyl-3-tetrahydropyranyloxy-4-                                                                Product d,l-erythro-1-iodo-3,4-iso-                     Example                                                                            hydroxy-1-alkyne of Example                                                                    propylidenedioxy-trans-1-alkene                         __________________________________________________________________________    83   78               d,l-erythro-1-ido-3,4-isopropyli-                                             denedioxy-trans-1-heptene                               84   79               d,l-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans-1-nonene                                85   80               d,l-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans-1-decene                                86   81               d,l-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-7-methyl-trans-1-octene                       87   82               d,l-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans,trans-1,5-octadiene                     __________________________________________________________________________

EXAMPLES 88-92

Acetylation of the 4-hydroxy group of thed,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkyneslisted in Table 9 below by the method described in Example 63, followedby hydrolysis of the resultingd,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-acetyloxy-1-alkynesto the correspondingd,1-erythro-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by themethod of Example 65, followed by epimerization tod,1-threo-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the methodof Example 66 followed by hydrolysis by the method of Example 67 to gived,1-threo-3,4-dihydroxy-1-alkynes are converted to the correspondingd,1-threo-3,4-isopropylidenedioxy-1-alkynes by treatment withdimethoxypropane in the presence of perchloric acid by the methoddescribed in Example 68 followed by treatment with disiamylborane,trimethylamine oxide, iodine, and sodium hydroxide solution by themethod described in Example 62 provides the productd,1-threo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 9 below.

                                      TABLE 9                                     __________________________________________________________________________         Starting d,l-erythro-1-trimethyl-                                             silyl-3-tetrahydropyranyloxy-4-                                                                Product d,l-threo-1-iodo-3,4-iso-                       Example                                                                            hydroxy-1-alkyne of Example                                                                    propylidenedioxy-trans-1-alkene                         __________________________________________________________________________    88   78               d,l-threo-1-iodo-3,4-isopropylidenedioxy-                                     trans-1-heptene                                         89   79               d,l-threo-1-iodo-3,4-isopropylidenedioxy-                                     trans-1-nonene                                          90   80               d,l-threo-1-iodo-3,4-isopropylidenedioxy-                                     trans-1-decene                                          91   81               d,l-threo-1-iodo-3,4-isopropylidenedioxy-                                     trans-1,7-methyl-1-octene                               92   82               d,l-threo-1-iodo-3,4-isopropylidenedioxy-                                     trans-1,5-trans-1-octadiene                             __________________________________________________________________________

EXAMPLE 93

A suspension of 24.3 g (1.0 mole) of magnesium in 90 ml of dry ether isstirred at room temperature under nitrogen with 100 mg of mercuricchloride. The reaction is initiated by the addition of 2 ml of propargylbromide and maintained by the dropwise addition of a solution of 119.5 g(1.0 mole) of propargyl bromide and 107.7 g (1.25 mole) of valenaldehydein 300 ml of dry ether. While the initial reaction is quite vigorous andis maintained at 30° C. only by cooling in an ice bath it may becomenecessary to heat the mixture to reflux temperature after about a thirdof the ether solution is added in order to maintain the reaction. Afterthe addition is complete the reaction mixture is refluxed until most ofthe magnesium is dissolved (several hours) and the reaction mixture isdecanted from excess magnesium into 1500 ml of stirred ice-cold ammoniumchloride solution. The ether layer is separated and the aqueous layer isextracted three times with 300 ml portions of ether. The combined etherextract is washed with saturated sodium chloride solution, dried overmagnesium sulfate and filtered. Evaporation of the ether under vacuumleaves about 115 g of yellow oil, which is distilled through a 15 cmVigreaux column at 18 mm. The fraction boiling at 81°-82° C. iscollected (36 g) and the higher-boiling and lower-boiling distillatesmay be redistilled to yield additional product. The infrared absorptionspectrum shows at most a trace of allene (5.1μ) and gas-liquid partitionchromatography shows a purity of about 98% for the main fraction.

EXAMPLES 94-97

The product 1-alkyn-4-ols of Table 10 below are prepared by treatment ofthe aldehydes listed in Table 10 with propargyl magnesium bromide by theprocedure described above in Example 93.

                  TABLE 10                                                        ______________________________________                                                                   Product                                            Example    Starting Aldehyde                                                                             1-alkyn-4-ol                                       ______________________________________                                        94         n-hexaldehyde   1-nonyn-4-ol                                       95         n-heptaldehyde  1-decyn-4-ol                                       96         n-butyraldehyde 1-heptyn-4-ol                                      97         3-cis-hexenaldehyde*                                                                          4-hydroxy-6-cis-                                                              ene-1-nonyne                                       ______________________________________                                         *M. Winter, Helv. Chim. Acta, 46, 1792 (1963).                           

EXAMPLE 98 Preparation of 4-triphenylmethoxy-1-octyne

A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [1. Crombie and A.G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g(0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine isheated on the steam bath for 2 hours. The cooled mixture is treated withwater and extracted with ether. The extract is washed successively withice cold 2% hydrochloric acid, saturated sodium chloride solution, driedwith magnesium sulfate, and taken to dryness. Column chromatography ofthe residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenichydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).

EXAMPLE 99 Preparation of 4-triphenylmethoxy-1-hexyne

A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-1-hexyne and 33.5g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine isheated at reflux for 2 hours. The cooled mixture is treated with waterand extracted with a hexane-ether mixture. The extract is washedsuccessively with water and saturated sodium chloride solution, diredover magnesium sulfate, and concentrated. Column chromatography of theresidue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600,1030 and 705 cm-1 (triphenylmethoxy group).

EXAMPLES 100-106

The triphenylmethoxy substituted 1-alkynes listed in Table 11 below areprepared by the method of Example 98 from triphenylmethyl bromide andthe corresponding hydroxy substituted 1-alkynes, appropriate literaturereferences to which are provided in the table.

                  TABLE 11                                                        ______________________________________                                        Ex-                                                                           am-  Reference to Starting                                                                            Product Triphenylmethoxy                              ple  Hydroxy Substituted 1-Alkyne                                                                     Substituted 1-Alkyne                                  ______________________________________                                        100  Reference 1        4-triphenylmethoxy-                                                           1-pentyne                                             101  Reference 1        4-triphenylmethoxy-                                        (Example 96)       1-heptyne                                             102  Reference 1        4-triphenylmethoxy-                                                           5-methyl-1-hexyne                                     103  Reference 2        4-triphenylmethoxy-                                        (Example 94)       1-nonyne                                              104  Reference 3        4-triphenylmethoxy-                                        (Example 95)       1-decyne                                              105  Reference 4        4-triphenylmethoxy-                                                           5-ethyl-1-heptyne                                     106  Example 97         4-triphenylmethoxy-                                                           6-cis-ene-1-nonyne                                    ______________________________________                                         Reference:                                                                    1. G. Fontaine, et al., Bull. Soc. Chem. France, 1447 (1963).                 2. S. Abe and K. Sato, Bull. Soc. Chem. Japan, 29, 88 (1956); Chem.           Abstr., 50, 13737 (1956).                                                     3. L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957);                  4. Nobuharra, Akio, Chem. Abstr., 70, 3219 (1969).   References: 1. G.        Fontaine, et al., Bull. Soc. Chem. France, 1447 (1963). 2. S. Abe and K.     Sato, Bull. Soc. Chem. Japan, 29, 88 (1956); Chem. Abstr., 50, 13737     (1956). 3. L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957); 4.     Nobuharra, Akio, Chem. Abstr., 70, 3219 (1969).

EXAMPLE 107 Preparation of 1-iodo-4-triphenylmethoxy-trans-1-octene

To a stirred suspension of 1.78 g (0.074 mole) of sodium borohydride in200 ml of dry glyme at -5° C. under nitrogen is added 15.8 g (0.22 mole)of 2-methyl-2-butene and 16.2 g (0.11 mole) of boron trifluorideetherate, and the mixture is stirred for 2 hours at -5° C. to 0° C. Asolution of 37.5 g (0.10 mole) of 4-trityloxy-1-octyne (Example 98) in50 ml of glyme is added to the cold solution during 5-10 minutes, andthe solution is allowed to warm to 20° C. during 1.5 hours. The reactionmixture is cooled to 0° C. and 30 g (0.4 mole) of drytrimethylamine-N-oxide is added during 5 minutes. On removing thecooling bath the temperature rises to 40° C. and the mixture is keptbetween 30°-40° C. for 1.5 hours. The suspension is poured rapidly intoone liter of ice cold 15% sodium hydroxide solution during good stirringand a solution of 80 g of iodine in 200 ml of tetrahydrofuran is addedimmediately. Stirring is continued for 30 minutes without furthercooling and the organic layer is separated. The aqueous layer isextracted with three 200 ml portions of ether and the combinded organiclayers are washed successively with water, 5% sodium thiosulfatesolution and saturated sodium chloride, dried over magnesium sulfate,filtered and evaporated to yield 50 g of yellow oil. The bulk of the oilis dissolved in hexane and, after decantation from a gummy solid thehexane solution is percolated through a 5.1 cm diameter column of 1500 gof alumina with additional hexane. Fractions containing the desiredproduct are concentrated to a pale yellow oil (33 g) which has n.m.r.and infrared spectra characteristics of the desired product.

EXAMPLES 108-115

Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table12 below with disiamylborane, prepared in situ from 2-methyl-2-butene,boron, trifluoride and sodium borohydride, followed by trimethylamineN-oxide, and then sodium hydroxide and iodine - all by the proceduredescribed in Example 107 above furnishes the product triphenylmethoxysubstituted 1-iodo-1-trans-alkenes of the table.

                  TABLE 12                                                        ______________________________________                                                 Starting Triphenyl-                                                                           Product 1-Iodo-tri-                                           methoxy Substituted                                                                           phenylmethoxysubsti-                                 Example  1-Alkyne of Example                                                                           tuted-1-trans-alkene                                 ______________________________________                                        108       99             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                                              hexene                                               109      100             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                                              pentene                                              110      101             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                                              heptene                                              111      102             1-iodo-4-triphenyl-                                                           methoxy-5-methyl-1-                                                           trans-hexene                                         112      103             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                                              nonene                                               113      104             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                                              decene                                               114      106             1-iodo-4-triphenyl-                                                           methoxy-1-trans-6-                                                            cis-nonadiene                                        ______________________________________                                    

EXAMPLES 116-124

The starting aldehydes or ketones of Table 13 below are converted to theproduct 1-alkyn-4-ols of the table by the procedure described in Example93.

                  TABLE 13                                                        ______________________________________                                               Starting                                                               Example                                                                              Aldehyde or Ketone                                                                          Product 1-Alkyn-4-ol                                     ______________________________________                                        115    2-octanone    4-methyl-4-hydroxy-1-decyne                              116    trans-2-hexenal                                                                             4-hydroxy-5-trans-nonen-1-yne                            117    2,2-dimethylhexanal                                                                         5,5-dimethyl-4-hydroxy-1-nonyne                          118    z-heptanone   4-methyl-4-hydroxy-1-nonyne                              119    2,2-dimethylpentanal                                                                        5,5-dimethyl-4-hydroxy-1-octyne                          120    2-methylpentanal                                                                            5-methyl-4-hydroxy-1-octyne                              121    2-methylhexanal                                                                             5-methyl-4-hydroxy-1-nonyne                              122    2-hexanone    4-hydroxy-4-methyl-1-octyne                              123    trans-3-hexen-2-one.sup.a                                                                   4-hydroxy-4-methyl-5-trans-                                                   octen-1-yne                                              124    trans-2-pentenal.sup.b                                                                      4-hydroxy-5-trans-octen-1-yne                             124a  trans-2-heptenal.sup.b                                                                      4-hydroxy-5-trans-decen-1-yne                            ______________________________________                                         .sup.a G. Startz, Bull. Soc. Chem. Fr., 1967, 2477.                           .sup.b R. I. Hoaglin and D. M. Hirsh, U.S. Pat. No. 2,628,257; Chem.          Abstr., 48, 1423e (1954).                                                

EXAMPLE 125 Preparation of 4-methyl-4-trimethylsilyloxy-1-octyne

To a stirred solution of 75.4 g (0.537 moles) of4-hydroxy-4-methyl-1-octyne (Example 122), 104.9 g (1.54 moles) ofimidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles)of chlorotrimethylsilane. After standing overnight the mixture is pouredinto 800 ml of hexane. The mixture is washed thoroughly with waterfollowed by sodium bicarbonate solution and brine. The solution is driedover magnesium sulfate, filtered, and evaporated to give a liquid, p.m.rspectrum, δ 1.26 (singlet, 3, CH₃), 1.92 (triplet, 1, HC), 2.30(doublet, 2, CH₂).

EXAMPLES 126-129

The 1-alkyn-4-ols of Table 14 are converted to the producttrimethylsilyl ethers of the table by treatment withchlorotrimethylsilane according to the procedure described in Example125.

                  TABLE 14                                                        ______________________________________                                        Ex-                     Product                                               ample Starting 1-alkyn-4-ol                                                                           Trimethylsilyl Ether                                  ______________________________________                                        126   5,5-dimethyl-4-hydroxy-1-                                                                       5,5-dimethyl-4-trimethylsi-                                 nonyne (Ex. 117)  lyloxy-1-nonyne                                       127   4-methyl-4-hydroxy-1-nonyne                                                                     4-methyl-4-trimethylsi-                                     (Ex. 118)         lyloxy-1-nonyne                                       128   5,5-dimethyl-4-hydroxy-1-                                                                       5,5-dimethyl-4-trimethylsi-                                 octyne (Ex. 119)  lyloxy-1-octyne                                       129   4-hydroxy-4-methyl-5-trans-                                                                     4-methyl-4-trimethylsi-                                     octen-1-yne (Ex. 123)                                                                           lyloxy-5-trans-octen-1-yne                             129a 4-hydroxy-4-methyl-1-decyne                                                                     4-methyl-4-trimethylsi-                                     (Ex. 124a)        lyloxy-1-decyne                                       ______________________________________                                    

EXAMPLE 130 Preparation of 1-iodo-4-hydroxy-4-methyl-trans-1-octene

To a stirred solution of 400 ml of 0.5 M bis-(3-methyl-2-butyl)borane inglyme, prepared from sodium borohydride, 2-methyl-2-butene, andboronitrifluoride etherate as in Example 107, is added 63.7 g (0.30moles) of 4-methyl-4-trimethylsilyloxy-1-octyne (Example 125) at -10° C.The solution is stirred at ambient temperature for 2.5 hours, cooled to-10° C., and treated during 30 minutes with 158 g (2.1 moles) of solidtrimethylamine oxide with cooling. The mixture is stirred at ambienttemperature for 2 hours and then poured into a stirred, ice-coldsolution of 15% aqueous sodium hydroxide; the stirred mixture is treatedimmediately with a solution of 426 g (1.68 moles) of iodine in 1100 mlof tetrahydrofuran. After 4 hours the mixture is extracted with ether.The extract is washed successively with water, aqueous sodiumthiosulfate, and brine and dried over magnesium sulfate. The extract isconcentrated, and the residue is subjected to chromatography on silicagel with hexane to provide an oil, p.m.r. (CDCl₃): δ 1.18 (singlet,4-CH₃ group).

EXAMPLES 131-134

The 4-trimethylsilyloxy-1-alkynes of Table 15 are converted to the4-hydroxy-1-iodo-trans-1-octenes of the table by the procedure describedin Example 130.

                  TABLE 15                                                        ______________________________________                                                Starting 4-Tri-                                                               methylsilyloxy-                                                               1-octyne of   Product 4-Hydroxy-1-iodo-                               Example Example       trans-1-octene                                          ______________________________________                                        131     126           1-iodo-5,5-dimethyl-4-hy-                                                     droxy-trans-1-nonene                                    132     127           1-iodo-4-methyl-4-hydroxy-                                                    trans-1-nonene                                          133     128           1-iodo-5,5-dimethyl-4-hy-                                                     droxy-trans-1-octene                                    134     129           1-iodo-4-methyl-4-hydroxy-                                                    trans,trans-1,5-octadiene                                134a    129a         1-iodo-4-methyl-4-hydroxy-                                                    trans-1-decene                                          ______________________________________                                    

EXAMPLE 135 Preparation of1-iodo-4-methyl-4-trimethylsilyloxy-trans-1-octene

To a stirred mixture of 24.5 g (55.6 mmoles) of1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g(100 mmoles) of chlorotrimethylsilane. After standing overnight themixture is poured into 250 ml of hexane. The mixture is washedthoroughly with water followed by brine and dried over magnesiumsulfate. After removal of the solvent, the product is distilled to givea colorless liquid, bp 67.5°-68° C. (0.07 mm).

EXAMPLES 136-139

The 1-iodo-4-hydroxy-trans-1-alkenes of Table 16 are converted to theproduct trimethylsilyl ethers of the table according to the proceduredescribed in Example 135.

                  TABLE 16                                                        ______________________________________                                                Starting 1-Iodo-4-                                                            hydroxy-trans-1-                                                                             Product Trimethylsilyl                                 Example alkene of Example                                                                            Ether                                                  ______________________________________                                        136     131            1-iodo-5,5-dimethyl-4-                                                        trimethylsilyloxy-                                                            trans-nonene                                           137     132            1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans-1                                                        nonene                                                 138     133            1-iodo-5,5-dimethyl-4-                                                        trimethylsilyloxy-                                                            trans-1-octene                                         139     134            1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans,-                                                        trans-1,5-octadiene                                     139a    134a          1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans-1-                                                       decene                                                  139b    134b          1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans-1-                                                       decene                                                 ______________________________________                                    

EXAMPLE 140 Preparation of 4-benzoyloxy-1-octyne

To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93)in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride.After stirring for 1.5 hours the mixture is treated with 10 ml of water,allowed to stand for 15 minutes, and concentrated. A solution of theresidue in ether is washed successively with ice-cold hydrochloric acid,water, sodium bicarbonate solution, and brine. The solution is driedover magnesium sulfate, filtered through Celite, and concentrated togive an oil, λ max. 3240 (terminal acetylene) and 1730 cm⁻¹ (benzyloxygroup).

EXAMPLE 141 Stereoselective Hydrolysis of Racemic 4-benzoyloxy-1-octyneby Rhizopus arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shakeflasks (250 ml Erlenmeyer). Each flask contains 50 ml of a mediumconsisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor inwater with pH adjusted to 7.0. A total of 14 such flasks are incubatedon a rotary shaker at 28° C. After 72 hours incubation, 50 mg of racemic4-benzoyloxy-1-octyne (Example 135) in 0.1 ml of acetone is added toeach flask. After 28 hours the flasks are harvested and worked up byextraction of the whole mash with an equal volume of chloroform. Thecombined extracts are dried over magnesium sulfate and concentrated. Theresulting oil is chromatographic on a column of silica gel with hexaneprogressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg of colorless oil, identical to4-benzoyloxy-1-octyne, [α]_(D) ²⁵ =5±1.0° (C═0.91, ethyl acetate). Thiscompound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg of colorless oil, identical to4-hydroxy-1-octyne, [α]_(D) ²⁵ =-17±1.0° (C═0.77, ethyl acetate). Thiscompound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher funguswhich grows steadily on a variety of artificial media at 20°-25° C. Inthis study of the taxonomic aspects of the culture, Petri dishes ofpotato-dextrose, malt extract, and cornmeal agars were inoculated andincubated at ambient room temperature for 10 days. Observations ofcultural and morphological characteristics are recorded in thedescription below:

Colonies on Petri dishes of potato-dextrose agar growing rapidly,covering the agar surface in 3-5 days and producing a thick, loose matof grayish mycelium. Colony surface characterized by abundant blacksporangia. Colony reverse grayish white. Colonies on malt extract agargrowing rapidly, covering the agar surface in 3-5 days. Mycelial matthick, grayish-yellow. Colony surface becoming brownish-black frommasses of sporangia. Colony reverse yellowish. Colonies on cornmeal agarvery thin, whitish; spreading across agar surface. Cultures transparentwith relatively few sporangia produced. Visibility of micromorphology isgood on this mediu. Rhizoids produced sparingly along stoloniferoushyphae. Generally two to three sporangiophores arose from rhizoids.Walls of sporangiophores olive brown, 14.0-20.0 μm in width at base,tapering slightly to apex; 0.5-1.5 mm in length Sporangiophoresterminated by spherical sporangia, 130-225 μm in diameter. Columellaehemispherical 3-50 μm high by 50-70 μm wide. Spores brownish whenmature, 6.0-8.5 μm×4.5-6.0 μm. Spore walls conspicuously marked bylongitudinal striations.

EXAMPLE 142 Preparation of (S)-4-hydroxy-1-octyne

A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyl-oxy-1-octyne (Example141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1methanol-water is allowed to stand at room temperature for 24 hours. Thebulk of the methanol is evaporated at room temprature, and the mixtureis extracted with ether. The extract is washed with brine, dried overmagnesium sulfate, and evaporated to give a colorless oil, identical to4-hydroxy-1-octyne [α]_(D) ²⁵ =+17±1.0° (C═0.77, ethyl acetate). Thiscompound has the (S)-configuration.

EXAMPLES 143-148

The starting 1-alkyn-4-ols of Table 17 below are converted to thetriphenylmethoxy substituted 1-alkynes by the method of Example 98.

                  TABLE 17                                                        ______________________________________                                                               Product Triphenyl-                                             Starting 1-Alkyn-                                                                            methoxy Substituted                                    Example 4-ol of Example                                                                              1-Alkyne                                               ______________________________________                                        143     116            4-triphenylmethoxy-5-                                                         trans-nonen-1-yne                                      144     120            5-methyl-4-triphenyl-                                                         methoxy-1-octyne                                       145     121            5-methyl-4-triphenyl-                                                         methoxy-1-nonyne                                       146     124            4-triphenylmethoxy-5-                                                         trans-octen-1-yne                                      147     141            (R)-4-triphenylmeth-                                                          oxy-1-octyne                                           148     142            (S)-4-triphenylmeth-                                                          oxy-1-octyne                                            148a    124a          4-triphenylmethoxy-5-                                                         trans-decen-1-yne                                      ______________________________________                                    

EXAMPLES 149-154

The product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of Table18 below are prepared from the starting triphenylmethoxy substituted1-alkynes of the table by the procedure described in Example 107.

                  TABLE 18                                                        ______________________________________                                             Starting Triphenyl-                                                                         Product                                                         methoxy Substituted                                                                         Triphenylmethoxy Substituted                               Ex.  1-Alkyn of Example                                                                          1-Iodo-trans-1-alkene                                      ______________________________________                                        149  143           1-iodo-4-triphenylmethoxy-trans,trans-                                        1,5-nonadiene                                              150  144           1-iodo-5-methyl-4-triphenylmethoxy-                                           trans-1-octene                                             151  145           1-iodo-5-methyl-4-triphenylmethoxy-                                           trans-1-nonene                                             152  146           1-iodo-4-triphenylmethoxy-trans,trans-                                        1,5-octadiene                                              153  147           (R)-1-iodo-4-triphenylmethoxy-1-trans-                                        octene                                                     154  148           (S)-1-iodo-4-triphenylmethoxy-1-trans-                                        octene                                                     154a  148a         1-iodo-4-triphenylmethoxy-trans,trans-                                        1,5-decadiene                                              ______________________________________                                    

EXAMPLE 155 Preparation of ethyl-p-fluorophenoxy-acetate

To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy aceticacid in one liter of absolute ethanol is added 10 ml of sulfuric acid.The mixture is heated to reflux for 18 hours, cooled to roomtemperature, and evaporated under vacuum. It is then poured onto 300 gof ice, extracted twice with 500 ml of ether, washed twice with 250 mlof a saturated solution of sodium bicarbonate, 100 ml of saturatedsodium chloride solution, dried with magnesium sulfate, filtered andevaporated under vacuum giving 58 g of an oil. This is crystallized from50 ml of hexane at -25° C. to give 55 g (90%) of the subject product ascolorless crystals, mp 32°-33° C.

EXAMPLE 156 Preparation of p-fluorophenoxy acetaldehyde

To a stirred solution of 1.98 g (10 mmoles) of ethyl-p-fluorophenoxyacetate (Example 155) in 15 ml of dry toluene, cooled to -78° C., underargon, is added, dropwise over 30 minutes, 8 ml of a 1.4 M solution ofdiisobutylaluminum hydride in toluene (11 mmoles). The mixture isstirred for 2 hours at -78° C., 1 ml of methanol is added, followed by 5ml of water, dropwise. The gel formed is filtered through Celite andwashed with 100 ml of ether, portionwise. The organic phase isseparated, washed twice with 25 ml of a saturated brine solution, driedwith magnesium sulfate, filtered, and evaporated. The oil obtained isdistilled at 71°-73° C. (0.1 mm) to give 600 mg (45%) of the subjectproduct as a colorless liquid.

EXAMPLE 157 Preparation of 3-hydroxy-4-p-flurorphenoxy-1-butyne

Acetylene gas, dried by passing through a trap containing sulfuric acid,is bubbled at a moderate rate, through 5 ml of vigorously stirredtetrahydrofuran, for 15 minutes. To this acetylenic solution, is thenadded dropwise, with continued passage of acetylene, 3.5 ml of a 2.4 Msolution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles)over 45 minutes. The mixture is stirred a further 15 minutes, and asolution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. Thissolution is stirred for 2 more hours, with passage of acetylene, pouredinto 50 ml of a saturated solution of ammonium chloride, extracted twicewith 50 ml of ether, washed with 10 ml of ammonium chloride solution,dried with magnesium sulfate, filtered, and evaporated. The crudesubject product is purified by sublimation at 75° C. (0.1 mm) for 5hours to give 330 mg (48%) of white crystals, mp 46°-47° C.

EXAMPLE 158 Preparation of4-p-fluorophenoxy-3-trimethylsilyloxy-1-butyne

To a 0° C. solution of 10 g (55 mmoles) of3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of drydimethylformamide and 88 g (130 mmoles) of imidazole is added dropwise,with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture,while under an argon atmosphere, is stirred at room temperature for 18hours, and then poured into 150 ml of hexane and 100 ml of ice-water.The organic phase is separated, washed with 50 ml of a brine solution,dried with magnesium sulfate, and evaporated under vacuum. This crudeproduct is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give12.2 g (91%) of the subject compound as a colorless oily liquid.

EXAMPLE 159 Preparation of1-tri-n-butylstannyl-4-p-fluorophenoxy-3-trimethylsilyloxy-trans-1-butene

A mixture of 2.52 g (10 mmoles) of3-trimethylsilyloxy-4-p-fluorophenoxy-1-butyne (Example 158), 2.91 g (10mmoles) of tri-n-butyl-tin hydride, and 10 mg of azobisisobutyronitrileis heated, under an argon atmosphere, with stirring, for 2 hours at 140°C. After cooling to room temperature, the crude reaction mixture isfractionally distilled at 180°-185° C. (0.05 mm), to give 4.6 g (85%) ofthe subject product as a colorless liquid.

EXAMPLES 160-162

The product esters of Table 19 below are obtained by the proceduredescribed in Example 155.

                  TABLE 19                                                        ______________________________________                                                Starting Aryloxy                                                                              Product Aryloxy                                       Example Acid            Ethyl Ester                                           ______________________________________                                        160     m-chlorophenoxy-                                                                              ethyl-m-chlorophenoxy-                                        acetic acid     acetate                                               161     3,4-dichlorophe-                                                                              ethyl-3,4-dichlorophe-                                        noxyacetic acid noxyacetate                                           162     phenoxyacetic acid                                                                            ethyl phenoxyacetate                                  ______________________________________                                    

EXAMPLE 163 Preparation of ethyl-m-trifluoromethylphenoxy-acetate

A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g(0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassiumcarbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, andat room temperature for 18 hours. The mixture is filtered, evaporatedunder vacuum on a rotarary evaporator at 45° C. and at 85° C. (0.1 mm)to remove excess ethyl bromoacetate. The reaction mixture is taken up in500 ml of ether, washed three times with 100 ml each of 0.1 M potassiumcarbonate, once with 100 ml of water, 100 ml of 0.01 M hydrochloricacid, and 100 ml of water. It is then dried with magnesium sulfate,filtered and evaporated, giving 142 g of the crude product. This isfractionally distilled at 73°-75° C. (0.1 mm) to give 124 g of thepurified subject product as a colorless liquid.

EXAMPLES 164-166

The product esters of Table 20 are obtained by treating the startingphenols with ethyl bromoacetate by the procedure of Example 162.

                  TABLE 20                                                        ______________________________________                                        Example Starting Phenol                                                                              Product Ester                                          ______________________________________                                        164     p-bromophenol  ethyl p-bromophenoxy-                                                         acetate                                                165     4-t-butylphenol                                                                              ethyl 4-t-butylphenoxy-                                                       acetate                                                166     p-methoxyphenol                                                                              ethyl p-methoxyphenoxy-                                                       acetic acid                                            ______________________________________                                    

EXAMPLES 167-173

Following the procedure of Example 156, the starting esters of Table 21are treated with diisobutylaluminum hydride to provide the productaldehydes of the table.

                  TABLE 21                                                        ______________________________________                                        Example Starting Ester                                                                              Product Aldehyde                                        ______________________________________                                        167     163           m-trifluoromethylphenoxy                                                      acetaldehyde                                            168     164           p-bromophenoxy acetalde-                                                      hyde                                                    169     165           4-t-butylphenoxy acetal-                                                      dehyde                                                  170     166           p-methoxyphenoxy acetalde-                                                    hyde                                                    171     160           m-chlorophenoxy acetalde-                                                     hyde                                                    172     161           3,4-dichlorophenoxy acet-                                                     aldehyde                                                173     162           phenoxyacetaldehyde                                     ______________________________________                                    

EXAMPLES 174-180

Following the procedure of Example 156, treatment of the startingaldehyde of Table 22 with acetylene magnesium chloride provides theproduct alkynes of Table 22.

                  TABLE 22                                                        ______________________________________                                                Starting                                                              Example Aldehyde   Product Aryloxy Alkyne                                     ______________________________________                                        174     167        3-hydroxy-4-m-trifluoromethyl-                                                phenoxy-1-butyne                                           175     168        3-hydroxy-4-p-bromophenoxy-1-                                                 butyne                                                     176     169        3-hydroxy-4-t-butylphenoxy-1-                                                 butyne                                                     177     170        3-hydroxy-4-p-methoxyphenoxy-                                                 1-butyne                                                   178     171        3-hydroxy-4-m-chlorophenoxy-                                                  1-butyne                                                   179     172        3-hydroxy-4-(3,4-dichlorophe-                                                 noxy)-1-butyne                                             180     173        3-hydroxy-4-phenoxy-1-butyne                                180a   a          3-hydroxy-5-phenyl-1-pentyne                                180b   b          3-hydroxy-5-(p-chlorophenyl)-                                                 1-pentyne                                                  180c    c          3-hydroxy-5-(p-methoxyphenyl)-                                                1-pentyne                                                   180d   d          3-hydroxy-5-(m-trifluorometh-                                                 ylphenyl)-1-pentyne                                        ______________________________________                                         a hydrocinnamaldehyde.sup.1                                                   b pchlorohydrocinnamaldehyde.sup.1                                            c pmetoxyhydrocinnnamaldehyde.sup.1                                           d mtrifluoromethylhydrocinnamaldehyde.sup.2                                   .sup.1 Billman, et al., Synthetic Communications, 1, 127-131 (1971).          .sup.2 Lednicer, Journ. Med. Chem., 11, 1258 (1968).                     

EXAMPLES 181-186

Treatment of the starting alkynes of Table 23 by the procedure ofExample 158 followed by treatment of the procedure of Example 159provides the product (E) 1-tri-n-butyltin-1-alkenes of the table.

                  TABLE 23                                                        ______________________________________                                        Ex-   Starting                                                                ample Alkyne   Product (E)-1-tri-n-butyltin-1-alkene                          ______________________________________                                        180   174      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                               m-trifluoromethylphenoxy-1-butene                              181   175      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                               p-bromophenoxy-1-butene                                        182   176      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                               t-butylphenoxy-1-butene                                        183   177      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                               p-methoxyphenoxy-1-butene                                      184   178      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                               m-chlorophenoxy-1-butene                                       185   179      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-                                 3,4-dichlorophenoxy-1-butene                                   186   180      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                               phenoxy-1-butene                                               186a   48      (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-                                  trimethylsilyloxy-(Z)-6-octadiene                              186b   180a    (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                               phenyl-1-pentene                                               186c   180b    (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                               (p-chlorophenyl)-1-pentene                                     186d   180c    (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                               (p-methoxyphenyl)-1-pentene                                    186e   180d    (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                               (m-trifluoromethylphenyl)-1-pentene                            ______________________________________                                    

EXAMPLE 187 Preparation of 1-chloro-1-octen-3-one

This compound is prepared according to the procedure of Price andPappalardo [C. C. Price and J. A. Pappalardo, Org. Syn, 32, 27(1952)]from hexanoyl chloride, acetylene, and aluminum chloride in 94%yield, bp 51°-52° C. (0.1mm); λ max 1680, 1595, 941 cm⁻¹.

EXAMPLE 188 Preparation of 1-iodo-1-octen-3-one

A mixture of 25g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187)and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone isstirred at the reflux temperature for 18 hours. The cooled mixture isfiltered and the mother liquor taken to dryness. The residual oil isdissolved in benzene and the solution is washed with 5% sodiumthiosulfate solution, saturated sodium chloride solution, dried andtaken to dryness. The residual oil is crystallized from hexane to give26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm⁻¹.

EXAMPLE 189 Preparation of 3-hydroxy-1-iodo-3-methyl-1-octene

To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesiumand 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether underargon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45ml of ether. The resulting solution is stirred at ambient temperaturefor one hour. After the addition of 75 ml of saturated ammonium chloridethe ether layer is separated and the aqueous layer is separated and theaqueous layer is extracted several times with ether. The combined etherextracts are washed successively with ammonium chloride and water, driedand taken to dryness to give 9.24 g of product as an oil; λ max 2,89,3,23,6.24 and 10.5.

EXAMPLE 190 Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-octene

To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1-octene(Example 184) and 7.4 g of imidazole in 45 ml of dry dimethylformamideis added dropwise 5.98 g of trimethylsilylchloride at 0° C. under argonatmosphere. After stirring at 0° C. for an additional 15 minutes, thesolution is stirred at ambient temperature for 18 hours. The reactionmixture is poured into 600 ml of hexane and the resulting solutionwashed with water, saturated sodium chloride solution, dried overanhydrous magnesium sulfate and taken to dryness to furnish 14.7 g ofoil. Distillation affords 13.4 g of clear oil; bp 65° C. (0.05 mm); λmax 6.21, 8.00, 9.90, 10.51, 11.90, 132μ.

EXAMPLE 190a Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-decene

Treatment of octanoylchloride by the procedures of Example 187 followedby treatment of the resulting 1-chloro-1-decen-3-one by the procedure ofExample 188 followed by treatment according to Examples 189 and 190 isproductive of the named compound.

EXAMPLE 191 Preparation of 4-trimethylsiloxy-1-octyne

To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10,289 (1975)], and 240 g of imidazole in one liter of dimethylformamide isadded dropwise 202 g of chlorotrimethylsilane. The mixture is allowed tostand at room temperature for 2to 3 days. The mixture is partitionedwith water and hexane. The hexane layer is washed with brine dried overmagnesium sulfate, and concentrated. Distillation of the residue gives acolorless liquid, bp 38° C. (0.2 mm).

EXAMPLE 192 preparation of 1-iodo-4-trimethylsiloxy-trans-1-octene

To a stirred solution of 0.20 moles of freshly preparedbis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5° C. isadded dropwise a solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30ml of tetrahydrofuran. The resulting mixture is stirred at ambienttemperature for several hours, cooled in an ice bath, and treated with53 g of trimethylamine oxide. The mixture is stirred several hours at25°-40° C. and then poured into 2 liters of 15% sodium hydroxide. Theresulting mixture is treated immediately with a solution of 140 g ofiodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase isseparated and the aqueous phase is extracted with ether. The combinedorganic layers are washed with water, sodium thiosulfate solution, andbrine; dried over magnesium sulfate; and concentrated to give an oil pmrspectrum (CDCl₃): 6.2 (d, ICH═) and 6.7 (quintuplet, ═CH-).

EXAMPLE 193 Preparation of 4-hydroxy-1-iodo-trans-1-octene

A 23 g portion of 1-iodo-4-trimethylsilyloxy-1-octene is dissolved in amixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and50 ml of water. Concentration provides the named product.

Example 194 Preparation of4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 456 mg of4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0mof dimethylformamide is added 0.23 ml of chlorotrimethylsilano during3minutes. The mixture is stirred at room temperature for 22 hours andpartitioned with a mixture of cold hexane and water. The hexane layer iswashed repeatedly with water and then brine, dried over magnesiumsulfate, and concentrated to give an oil, pmr spectrum (CDCl₃): 0.13 (s,trimethylsiloxy group) and 2.32 (d, ═CHCH₂).

EXAMPLE 195 Preparation of n-butyl cyclopropyl ketone

To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylicacid in 330 ml of ether is added a solution of n-butyllithium (748mmoles) in about 750 ml of 2:1 etherhexane during one hour at 5°-10° C.The resulting suspension is diluted with 300 ml of ether and stirred atroom temperature for 2 hours and at reflux for 2 hours. The mixture iscooled and poured into several portions of 1:1 ice:4N hydrochloric acid.The ethereal phases are combined and washed with brine, sodium carbonatesolution, and brine. The extract is dried over magnesium sulfate andconcentrated. The residue is distilled to provide a liquid, bp-102°-104°C. (80 mm), pmr spectrum (CDC1₃): δ 2.55 (triplet, --CH₂ CO--).

EXAMPLE 196 Preparation of 4-cyclopropyl-4-hydroxy-1-octyne

To a stirred, refluxing suspension of amalgum prepared from 6.2 g ofmagnesium and 50 mg of mercuric chloride suspended in 60 ml of ether isadded a solution of a mixture of 30.4 g of n-butyl cycloproxyl ketone(Example 189) and 29.8 g of propargyl bromide in 65 ml of ether during60 minutes. After reaction at reflux temperature for an additional 30minutes, the mixture is cooled to 0° C. and treated with 35 ml ofsaturated ammonium chloride. The mixture is diluted with ether andfiltered through Celite. The filtrate is washed with brine, dried overpotassium carbonate, and concentrated. The residue is distilled toprovide a liquid, δ 0.43 (cyclopropyl hydrogens), 2.07 (triplet, HC.tbd.C.), and 2.44 (doublet, C.tbd.CCH₂).

EXAMPLE 197 Preparation of 4-cyclopropyl-4-trimethylsiloxy-1-octyne

To a stirred solution of 27.8 g of 4-cyclopropyl-4-hydroxy-1-octyne(Example 190) and 33.3 g of imidazole in 130 ml of dimethylformamide at5° C. is added 24 ml of chlorotrimethylsilane during 5 minutes. Thesolution is stirred at ambient temperature for 17 hours and thenpartitioned with 600 ml of hexane and 250 ml of ice water. The hexanephase is separated and washed successively with water and brine. Thesolution is dried over magnesium sulfate and evaporated to give aliquid, pmr spectrum (CDC1₃ : δ 0.12 (singlet, trimethylsiloxy group),2.02 (triplet, HC.tbd.C.), and 2.45 (doublet, C.tbd.CH₂).

EXAMPLE 198 Preparation of4-cyclopropyl-4-trimethylsiloxy-1-(tri-n-butylstannyl)-trans-1-octene

A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne(Example 191), 28 ml of tri-n-butyltin hydride, and 50 mg ofazobisisobutyronitrile under nitrogen is heated to 85° C. After theresulting exothermic reaction subsides the mixture is heated at 130° C.for one hour. The crude product is evaporatively distilled to give aliquid, pmr spectrum (CDC1₃): δ 0.10 (trimethylsiloxy group), 2.33(doublet, ═CHCH₂), and 6.02 (vinyl hydrogens).

EXAMPLES 199-204

Treatment of the starting carboxylic acids of Table 24 with theappropriate alkyllithium by the method of Example 190 provides theproduct ketones of the table.

                  TABLE 24                                                        ______________________________________                                             Starting                                                                      Carboxylic                                                               Ex.  Acid        Alkyl Lithium                                                                              Product Ketone                                  ______________________________________                                        199  cyclopropane                                                                              n-hexyllithium                                                                             n-hexylcyclopropyl                                   carboxylic acid          ketone                                          200  cyclopropane                                                                              n-propyllithium                                                                            n-propylcyclopropyl                                  carboxylic acid          ketone                                          201  acrylic acid                                                                              n-hexyllithium                                                                             n-hexylvinyl ketone                             202  acrylic acid                                                                              n-propyllithium                                                                            n-propylvinyl ketone                            203  crotonic acid                                                                             n-butyllithium                                                                             n-butyl-1-propenyl                                                            ketone                                          204  crotonic acid                                                                             n-hexyllithium                                                                             n-hexyl-1-propenyl-                                                           ketone                                          204a acrylic acid                                                                              n-butyllithium                                                                             n-butylvinyl ketone                             ______________________________________                                    

EXAMPLES 205-210 e

Treatment of the starting ketones of Table 25 with propargymagnesiumbromide by the procedure of Example 190 followed by treatment withchlorotrimethylsilane by the procedure of Example 191 followed bytreatment with tri-n-butyl-tin hydride by the method of Example 192 isproductive of the vinylstannyl derivatives of the table.

                  TABLE 25                                                        ______________________________________                                               Starting                                                               Example                                                                              Ketone     Product Vinylstannyl Derivative                             ______________________________________                                        205    199        (E)4-trimethylsilyloxy-4-cyclopropyl-1-                                       tri-n-butylstannyldecene                                    206    200        (E)4-trimethylsilyloxy-4-cyclopropyl-1-                                       tri-n-butylstannylheptene                                   207    201        (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                       butylstannyldecene                                          208    202        (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                       butylstannylheptene                                         209    203        (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                                      tri-n-butylstannyloctene                                    210    204        (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                                      tri-n-butylstannyldecene                                     210a   204a      (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                       butylstannyloctene                                           210b  2-hexanone (E)-4-trimethylsilyloxy-4-methyl-1-tri-n-                                     butylstannyloctene                                           210c  3-heptanone                                                                              (E)-4-trimethylsilyloxy-4-ethyl-1-tri-n-                                      butylstannyloctene                                           210d  3-octanone (E)-4-trimethylsilyloxy-4-ethyl-1-tri-n-                                      butylstannylnonene                                           210e  3-hexanone (E)-4-trimethylsilyloxy-4-ethyl-1-tri-n-                                      butylstannylheptene                                         ______________________________________                                    

EXAMPLE 211 Preparation oftrans-1-Hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane

A mixture of 88 g of cyclopentene oxide, 150.7 g of3-trifluoromethylphenyl, 5.0 g of sodium hydroxide in 30 ml of water and4.0 g of methyltricaprylyl ammonium chloride is stirred at 70°-80° C.for 51 hours and at 25° C. for 96 hours. The mixture is then dilutedwith methylene chloride and poured into water. The organic layer iswashed with dilute sodium hydroxide solution and water. The solution isdried over magnesium sulfate. The solvent is removed giving 221.5 g of aliquid which is distilled (bp 110°-113° C. 0.8 mm) givingtrans-1-hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane.

EXAMPLE 212

In the manner desribed above in Example 211 from 4-flourophenol andcyclopentane epoxide is preparedtrans-1-hydroxy-2-(4-fluoro)phenoxycyclopentane.

EXAMPLE 213

In the manner described above in Example 211 from 3-chlorophenol andcyclopentane epoxide is preparedtrans-1-hydroxy-2-(3-chloro)phenoxycyclopentane. EXAMPLE 214

Preparation of 2-(3-Trifluoromethylphenoxy)cyclopentanone

To a suspension of 327.43 g of pyridinium chlorochromate in one liter ofmethylene chloride is added 220 g oftrans-1-hydroxy-2-(3-trifluoromethylphenoxy) cyclopentane in 500 ml ofmethylene chloride. The mixture is stirred for 2hours 15 minutes.Another 50 g of the oxidizing agent is added and the mixture is stirredfor 41/2hours. The mixture is diluted with ether and decanted from ablack residue which is washed with more ether. The combined solutionsare filtered through silica gel. The solvent is removed. The residue isdissolved in ether and again filtered through silica-gel. The solvent isremoved and the residue is distilled (bp 113°-116° C. 1.5 mm) to give188 g of 2-(b 3-trifluoromethylphenoxy)cyclopentanone.

EXAMPLE 215

In the manner described above for Example 214 is prepared from theproduct of Example 212; 2-(4-(fluorophenoxy)cyclopentanone.

EXAMPLE 216

In the manner described above for Example 214 is prepared from theproduct of Example 213; 2-(3-chlorophenoxy)cyclopentanone.

EXAMPLE 217 Preparation of 1R,2S(and1S,2R)-1-Ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane

Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as asolution of 2.4M n-butyl magnesium chloroide (92ml) is added dropwisewith stirring over a 2-hour period. To the resulting solution ofacetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in50 ml of tetrahydrofuran dropwise over 15 minutes. The solution isstirred for 30 minutes and then is poured into an ice cold solution ofsaturated ammonium chloride. The mixture is acidified to pH 5 andextracted with ether. The ether solution is washed with brine and driedover magnesium chloride. The ether is removed and the residue isdistilled giving 14.8 g of colorless liquid. This is chromatographed ona dry column of silica-gel eluting with benzene-ethyl acetate (19:1) toseparate isomers giving 1R,2S(and1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane.

EXAMPLE 218 Preparation of 1-propargyl-1-hydroxycyclohexane

A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1 ofanhydrous ether is treated with 0.6 g of mercuric chloride and about 100mg of iodine. After several minutes, 3ml of propargyl bromide is addedand if no exotherm is noted, a small amount of reacting propargylbromide and magnesium in ether is added. With the reaction begins, amixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargylbromide is added dropwise at a rate that produces vigorous refluxing ofsolution. (The propargyl bromide must always by present in some excessotherwise the reaction will stop. If this happens, the addition of about1 ml of propargyl bromide will restart the reaction.) After about halfof the propargyl bromide-cyclohexanone mixture has been added, another500-750 ml of ether is used to dilute the reaction mixture. At the endof the addition, the reaction mixture is refluxed for at least 0.5hours, cooled and poured into 4 liters of saturated ammonium chlorideduring good stirring. The ethereal layer is separated and the aqueouslayer is washed with ether several times and the combined extract iswashed twice with saturated sodium chloride solution and dried overanhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630g theory) of a dark oil which is distilled giving purified 1propargyl-1-hydroxycyclohexane.

EXAMPLES 219-238

In the manner of Examples 217 and 218 described above the followingacetylenic alcohols listed in Table 26 were prepared from the acetylenicGrignard reagent and ketone specified.

                                      TABLE 26                                    __________________________________________________________________________    Example                                                                            Grignard Reagent                                                                       Ketone      Acetylenic Alcohol                                  __________________________________________________________________________    219  acetylene magne-                                                                       cyclohexanone                                                                             1-ethynyl-1-hydroxycyclohexane                           sium chloride                                                            220  acetylene magne-                                                                       cyclopentanone                                                                            1-ethynyl-1-hydroxycyclopentane                          sium chloride                                                            221  acetylene magne-                                                                       cycloheptanone                                                                            1-ethynyl-1-hydroxycycloheptane                          sium chloride                                                            222  acetylene magne-                                                                       3-propylcyclopentanone                                                                    1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                  sium chloride        3-propylcyclopentane                                223  acetylene magne-                                                                       3-propylcyclopentanone                                                                    1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                  sium chloride        3-propylcyclopentane                                224  acetylene magne-                                                                       2-butylcyclohexanone                                                                      1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride        2-butylcyclohexane                                  225  acetylene magne-                                                                       2-butylcyclohexanone                                                                      1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride        2-butylcyclohexane                                  226  acetylene magne-                                                                       2-(3-trifluoro-                                                                           1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy) cyclopen-                            cyclopentanone                                                                            tane                                                227  acetylene magne-                                                                       2-(3-trifluoro-                                                                           1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy) cyclopentane                         cyclopentanone                                                  228  acetylene magne-                                                                       2-(4-fluorophen-                                                                          1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          oxy) cyclopentanone                                                                       2-(4-fluorophenoxy) cyclopentane                    229  acetylene magne-                                                                       2-(4-fluorophen-                                                                          1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          oxy) cyclopentanone                                                                       2-(4-fluorophenoxy) cyclopentane                    230  acetylene magne-                                                                       2-(3-chlorophenoxy)-                                                                      1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          cyclopentanone                                                                            2-(3-chlorophenoxy) cyclopentane                    231  acetylene magne-                                                                       2-(3-chlorophenoxy)-                                                                      1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          cyclopentanone                                                                            2-(3-chlorophenoxy) cyclopentane                    232  acetylene magne-                                                                       3-methylcyclohexa-                                                                        1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          none        3-methylcyclohexane                                 234  acetylene magne-                                                                       3-methylcyclohexa-                                                                        1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          none        3-methylcyclohexane                                 235  propargyl magne-                                                                       2-butylcyclopenta-                                                                        1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                sium bromide                                                                           none        2-butylcyclopentane                                 236  propargyl magne-                                                                       2-butylcyclopenta-                                                                        1R,2R-(and 1S,2S-) 1-propargyl-1-hydroxy-                sium bromide                                                                           none        2-butylcyclopentane                                 237  propargyl magne-                                                                       2-(3-trifluoro-                                                                           1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                sium bromide                                                                           methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy) cyclopentane                         cyclopentanone                                                  238  propargyl magne-                                                                       2-(3-trifluoro-                                                                           1R,2R-(and 1S,2S-) 1-propargyl-1-hydroxy-                sium bromide                                                                           methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy) cyclopentane                         cyclopentanone                                                  __________________________________________________________________________

EXAMPLE 239 Preparation of 1R,2S(and1S,2R)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a solution of 29.4 g of 1R,2S(and1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazolein 180 ml of dimethylformamide is added at 0° C. with stirring 24.1 g oftrimethylsilylchloride. The mixture is stirred for 3 hours. The mixtureis poured into 700 ml of hexane and washed twice with water and oncewith brine. The ether solution is dried over magnesium sulfate. Thesolvent is removed and the residue is distilled (bp 64°-72° C., 0.6 mm)to give 35.8 g of 1R,2S(and1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 240 Preparation of 1R,2R(and1S,2S)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 45.0 g of 1R,2R(and1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 46.2 g of imidazolein 255 ml of dimethylformamide at 0° C. under nitrogen is added 36.9 oftrimethylsilylchloride. The mixture is stirred at room temperature for 3hours and then poured into 700 ml of hexane. Water is added, the organiclayer is separated and the water layer is extracted with hexane. Thecombined hexane solutions are washed twice with water and dried overmagnesium sulfate. The solvent is removed and the residue is distilledgiving the product as 53 g of a colorless oil.

EXAMPLE 241 Preparation of 1-Ethynyl-1-trimethylsilyloxycyclohexane

A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol aremixed with 500 g of dimethylformamide with cooling in an ice bath. A 152g portion of trimethylchlorosilane is added with cooling and stirring inabout one minute. The mixture is stirred for one hour and allowed tostand overnight. One liter of hexane is added. The lower layer isseparated, diluted with water and extracted with hexane. The hexanelayers are washed several times with water and then combined and driedover magnesium sulfate. Filtration and then evaporation of the hexanegives 198.5 g of product which is distilled giving 168 g of the desiredproduct.

EXAMPLE 242 Preparation of 1-Propargyl-1-trimethylsilyloxycyclohexane

To a stirred solution of 55.4 g of 1-(2-propyn-1-yl)cyclohexanol [H.Gutmann, et al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazolein 240 ml of DMF at 10° C. initially is added 56 ml ofchlorodimethylsilane during 10 minutes. The cloudy yellow solution isstirred at room temperature for 26 hours. The resulting mixture ispartitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C.The hexane phase is washed successively with 6×200 ml of cold water and200 ml of brine. The extract is dried over magnesium sulfate, filtered,and evaporated to give 85 g of colorless liquid, i.r. (film) :1240 and830 cm⁻¹ (trimethylsilyloxy group).

EXAMPLE 243 Preparation of 1R,2S(and1S,2R)-1-(trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 9.2 g of sodium borohydride and 45.8 g of2-methyl-2-butene in 350 ml of dry tetrahydrofuranat 0° C. with stirringunder nitrogen is added, over 20 minutes, 41.1 ml of boron trifluorideetherate. After 3 hours, to this resulting solution of diisomaylboraneis added 38.8 g of 1R,2S(and1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butycyclopentane in 40 ml oftetrahydrofuran in 20 minutes. The mixture is stirred 2 hours and thenstored at -20° C. overnight. The mixture is allowed to warm to 0°C. andat 0°C.85 g of dry trimethylamineoxide is added portionwise over 20minutes. After stirring at 25° C. for one hour, the mixture is filteredthrough diatomaceous earth. The filtrate is poured simultaneously with asolution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred,cold solution of 430 g of sodium hydroxide in 1900 ml of water. Afterstirring for 30 minutes, the organic layer is separated. The aqueouslayer is extracted with ether. The combined organic solutions are washedtwice with a saturated solution of sodium thiosulfate and once withbrine. The solution is dried over magnesium sulfate, the solvent isremoved and the residue is dissolved in hexane. The hexane solution isfiltered through diatomaceous earth and silica gel. The hexane isremoved and the residue is purified by dry column chromatography onsilica gel eluting with hexane: 45.35 g of 1R,2S(and1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane isobtained.

EXAMPLE 244 Preparation of 1R,2R(and 1S,2S)-1-(trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butycyclopentane

To a mixture of 12.22 g of sodium borohydride and 60.82 g of2-methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0° C.,is added 54.6 ml of boron trifluoride ehterate, dropwise over a 20minute period. The solution is stirred at 0° C. for 2 hours and then atroom temperature for 30 minutes. This solution is cooled to 0° C. and55.5 g of 1R,2R(and1S,2S)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 50 ml oftetrahydrofuran is added. The mixture is allowed to stand in a cold roomovernight. To this mixture at 0° C. is added with stirring 112.8 g oftrimethylamine oxide over a 20 minute period. The mixture is stirred atroom temperature for 90 minutes and then filtered. To the filtrate isadded simultaneously a solution of 565 g of sodium hydroxide in 2000 mlof water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran.The mixture is stirred 30 minutes, the organic layer is separated andthe aqueous layer is extracted with ether. The combined organicsolutions are washed with saturated sodium thiosulfate solution and withsaturated sodium chloride solution. The solution is dried with magnesiumsulfate and filtered through a pad of silica gel. The solution isremoved giving an orange liquid which is chromatographed on a dry columnof silica gel giving 59.5 g of the product as a yellow liquid.

EXAMPLE 245 Preparation of1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg ofazobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. Thestirred mixture is heated to about 80° C. The initial exothermicreaction is moderated, and the temperature is subsequently maintained at130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLES 246-265 Using the procedure outlined above for Examples239-242, the acetylenic alcohols listed in Table 27 are converted totheir corresponding acetylenic trimethylsilyloxy derivative, these inturn using the procedure outlined above for Examples 243 and 244, wereconverted to their corresponding trans-2-iodovinyl derivatives or usingthe procedure outlined above for Example 245, were converted to theircorresponding trans-2-tri-n-butylstannyl derivatives (Table 27).

                                      TABLE 27                                    __________________________________________________________________________    Example                                                                            Acetylene of Example                                                                     Method of Example                                                                       Vinyl Iodide or Vinyl Tin Compound                  __________________________________________________________________________    246  219        244       1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                    cyclohexane                                         247  220        244       1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                    cyclopentane                                        248  221        245       1-(trans-2-tri-n-butylstannylvinyl)-1-tri-                                    methylsilyloxycycloheptane                          249  222        244       1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-propylcyclopentane              250  223        244       1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-propylcyclopentane              251  217        244       1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-2-butylcyclopentane               252  224        244       1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-2-butylcyclohexane                253  225        244       1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-2-butylcyclohexane                254  226        245       1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy-2-(3-                                       trifluoromethylphenoxy) cyclopentane                255  227        245       1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy-2-(3-tri-                                   fluoromethylphenoxy) cyclopentane                   256  228        244       1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-                                     1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                      cyclopentane                                        257  229        244       1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-                                     1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                      cyclopentane                                        258  230        245       IR,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy-2-(3-                                       chlorophenoxy) cyclopentane                         259  231        245       IR,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl                                     stannylvinyl)-1-trimethylsilyoxy-2-(3-                                        chlorophenoxy) cyclopentane                         260  232        244       1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                   trimethysilyloxy-2-methylcyclohexane                261  234        244       1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-methylcyclohexane               262  235        245       1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      butylcyclopentane                                   263  236        245       1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      butylcyclopentane                                   264  237        245       1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      (3-trifluoromethylphenoxy) cyclopentane             265  238        245       1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      (3-trifluoromethylphenoxy) cyclopentane             __________________________________________________________________________

The ring system of the novel compounds of this invention allow them tobe characterized as follows: ##STR144##

The novel compounds of this invention possess the pharmacologicalactivity described below as associated prostaglandins of the PGE-Type.

The known PGE compounds are all potent in causing multiple biologicalresponses even at low doses. For example, PGE₁ and PGE₂ are extremelypotent in causing vasodepression and smooth muscle stimulation, and alsoare potent as antilipolytic agents. Moreover, for many applications,these known prostaglandins have an inconveniently short duration ofbiological activity. In striking contrast, the novel prostaglandinanalogs of this invention are substantially more specific with regard topotency in causing prostaglandin-like biological responses, and/orhaving a substantially longer duration of biological activity.Therefore, each of these novel prostaglandin analogs is surprisingly andunexpectedly more useful than one of the corresponding above-mentionedknown prostaglandins for at least one of the pharmacological purposesindicated below for the latter, either because it has a different andnarrower spectrum of biological activity than the known prostaglandins,and therefore is more specific in its activity and causes smaller andfewer undesired side effects than the known prostaglandins, or becauseof its prolonged activity, fewer and smaller doses of the novelprostaglandin analog can frequently be used to attain the desiredresult.

The 11-deoxy-PGE compounds are additionally selective in that they areat most relatively very weak stimulants of smooth muscle. The 11-deoxyPGE compounds have a further advantage in that they are much more stableand have a longer "shelf-life" than the corresponding 11-hydroxyderivatives as described more fully hereinbelow.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively, orally, sublingually, intravaginally, bucally,topically, or rectally, in addition to the usual intravenous,intramuscular, or subcutaneous injection or infusion methods indicatedabove for the uses of the known prostaglandins. These qualities areadvantageous because they facilitate maintaining uniform levels of thesecompounds in the body with fewer, shorter, or smaller doses, and makepossible self-administration by the patient.

PGE₁, PGE₂, PGE₃, and dihydro-PGE₁ and their esters andpharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom, etal., Pharmacol. Rev., 20, 1 (1968), and references cited therein. A fewof those biological responses are systemic arterial blood pressurelowering in the case of the PGE compounds as measured, for example, inanesthetized (phenobarbital sodium) pentolinium-treated rats withindwelling aortic and right heart cannulas; stimulation of smooth muscleas shown, for example by tests on strips or guinea pig ileum, rabbitduodenum, or gerbil colon; potentiation of other smooth musclestimulants; antilipolytic activity as shown by antagonism ofepineephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE compounds asshown in dogs with secretion stimulated by food or histamine infusion;activity on the central nervous system; decrease of blood plateletadhesiveness in the case of PGE, as shown by platelet-to-glassadhesiveness, and inhibition of blood platelet aggregation and thrombusformation induced by various physical stimuli, e.g., arterial injury,and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin,and collagen and in the case of the PGE compounds, stimulation ofepidermal proliferation and keratinization as shown when applied inculture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdisease and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg to about10 mg per ml of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE compounds are useful in mammals, including man and certainuseful animals, e.g., dogs and pigs, to reduce and control excessivegastric secretion, thereby reducing or avoiding gastric erosion orgastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 μg to about 500 μgper kg of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg per kg of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.These compounds may also be useful in conjunction with variousnon-steroidal anti-inflammatory agents, such as aspirin, phenylbutazone,indomethacin and the like, to minimize the well-known ulcerogeniceffects of the latter.

The PGE₁ compounds are useful whenever it is desired to inhibit plateletaggregation, to reduce the adhesive character of platelets, and toremove or prevent the formation of thrombi in mammals, including man,rabbits, and rats. For example, these compounds are useful in treatmentand prevention of myocardial infarcts, to treat and preventpost-operative thrombosis. For these purposes, these compounds areadministered systemically, e.g., intravenously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred. Doses in the range ofabout 0.005 to about 20 mg per kg of body weight per day are used, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration.

11α-Hydroxy-PGE compounds are extremely potent in causing stimulation ofsmooth muscle, and are also highly active in potentiating other knownsmooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin,and the various ergot alkaloids including derivatives and analogsthereof. Therefore PGE₂, for example, is useful in place of or incombination with less than usual amounts of these known smooth musclestimulators, for example, to relieve the symptoms of paralytic ileus, roto control or prevent uterine bleeding after abortion or delivery, toaid in expulsion of the placenta, and during the puerperium. For thelatter purpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 μg per kg of body weight per minute until the desired effectis obtained. Subsequent doses are given by intravenous, subcutaneous, orintramuscular injection or infusion during puerperium in the range of0.01 to 2 mg per kg of body weight per day, the exact dose depending onthe age, weight, and condition of the patient or animal.

The PGE compounds are useful as hypotensive agents to reduce bloodpressure in mammals including man. For this purpose, the compounds areadministered by intravenous infusion at the rate about 0.01 to about 50μg per kg of body weight per minute, or in a single or multiple doses ofabout 25 to 2500 μg per kg of body weight total per day.

The PGE compounds are useful in place of oxytoxin to induce labor inpregnant female animals, including man, cows, sheep, pigs, at or nearterm or in pregnant animals with intrauterine death of the fetus fromabout 20 weeks to term. For this purpose, the compound is infusedintravenously at a dose 0.01 to 50 μg per kg of body weight per minuteuntil or near the termination of the second stage of labor, ie.,expulsion of the fetus. These compounds are especially useful when thefemale is one or more weeks postmature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started.

The PGE compounds are useful for controlling the reproductive cycle inovulating female mammals, including humans and other animals. For thatpurpose, a PGE compound is administered systematically at a dose levelin the range of 0.01 mg to about 50 mg per kg of body weight,advantageously during a span of time starting approximately at the timeof ovulation and ending approximately at the time of menses or justprior to menses. Additionally, expulsion of an embryo or fetus isaccomplished by similar administration of the compound during the firstthird or the second third of the normal mammalian gestation period.Accordingly they are useful as abortifacients. They are also useful forinduction of menses during approximately the first two weeks of a missedmenstrual period and accordingly are useful as contraceptiveanti-fertility agents.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate a wet dressing for topical application to second and/or thirddegree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containingone to 500 μg/ml of the PGB compound or several times that concentrationof the PGE compound. Especially for topical use, these prostaglandinsare useful in combination with antibiotics, for example, gentamycin,neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The compounds of this invention are also useful as topical vasodilators.

The novel compounds of this invention induce the biological responsesdescribed hereinabove as associated with its particular prostaglandintype. These novel compounds are accordingly useful for theabove-described corresponding purposes in the same manner as describedabove.

The novel PGE compounds of this invention are also useful asbronchodilators for the treatment of asthma and chronic bronchitis; assuch they may be conveniently administered by inhalation of aerosolsprays prepared in a dose range of about 10 μg to about 10 mg per ml ofa pharmacologically suitable liquid vehicle.

These derivatives described hereinabove are also more selective in theirbiological action and generally induce a more prolonged effect than thecorresponding natural prostaglandins. These preparations are novel,completely unanticipated and provide distinct and important advantages.

In addition, certain of the novel compounds of this invention are usefulfor the preparation of other novel compounds of this invention.

It is well known that platelet aggregation inhibitors may be useful asanti-thrombotic drugs. Inhibition of platelet aggregation can beconveniently measure in vitro by monitoring changes in optical densityand/or light transmission in platelet rich plasma upon addition ofsuitable aggregating agents such as adenosine diphosphate, epinephrine,thrombin or collagen. Alternatively, platelet aggregation can bemeasured in vitro using platelet rich plasma obtained at various timeintervales from animals given inhibitors by an oral or parenteral route.

The compounds of the present invention exhibit the ability to inhibitplatelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solutionin a proportion of 40-50% human protein rich plasma. The test compoundsare added at varying concentrations and after 5 minutes incubation, anaggregating agent such as adenosine diphosphate or collagen is added.The change in optical density (light transmission) is monitored by eyeand inhibition is recorded as a (-) or lack of inhibition is recorded asa (+). Test compounds are considered active if they inhibit adenosinediphosphate or collagen induced aggregation at a concentration of 0.025mg/ml or less within 5-10 minutes. For example, a compound of thisinvention, 1,9-dioxo-15-hydroxy-1-hydroxymethyl-13-trans-prostene, showsinhibition of platelet aggregation induced by both adenosine diphosphateand collagen at a concentration of 0.025 mg/ml.

The compounds of this invention have bronchodilator activity asdetermined in a test using dogs anesthetized, artificially ventilatedand submitted to a continuous respiratory spasm induced by pilocarpine.

Mongrel dogs of either sex weighing between 5 and 10 kg are used. Theyare premedicated with morphine HCl by subcutaneous injection at 1.5mg/kg. An intravenous perfusion of 5%(W/V) chloralose is started 1/2hour after the morphine injection in such a way that 60 mg/kg areadministered within 15 minutes. After completion, a continuous perfusionof 10 mg/kg/hour is maintained throughout the experiment. The dogs areartificially ventilated by means of a Starling pump at a rate of 20breaths/minute. The volume is adjusted according to the weight of theanimal. [Kleinman and Radford, J. Appl. Physiol., 19, 360 (1964)]. Allthe measurements are made with the dogs positioned supine in a heated,V-shaped table. Curarization is obtained by succinylcholine chlorideusing a starting injection of 3 mg/kg lasting 3 minutes, followed by acontinuous perfusion of 0.1 mg/kg/minute.

The respiratory spasm is induced by a starting injection of 400 mcg/kgof pilocarpine HCl lasting 5 minutes. An increase or decrease of theinjected dose of pilocarpine HCl may occur as a function of the observedeffect on the airways resistance. A 15 minute delay is observed beforethe start of a continuous perfusion of pilocarpine HCl at a dose of 4mcg/kg/minute to maintain a constant spasm during the test.

A metallic cannula is inserted and fixed, after tracheotomy, into theupper part of the trachea. The two cophalic veins and the two femoralveins are catheterized to inject the various agents. The femoral arteryis catheterized to measure the systemic blood pressure. An oesophagealballoon (11 cm×2.5 cm) is inserted into the lower third of theoesophagus to measure the endothoracic pressure. The measurement of airflow is made with a Fleish pneumotachograph connected to the trachealtube.

The transpulmonary pressure is measured as follows: The tracheal cannulais equipped with a stainless steel axial tube (1.5 mm) which is closedat its distal end and projected 2.5 cm beyond the end of the cannula.Three holes with a diameter of one mm are pierced on this lattersegment. This tube, which is used to measure the tracheal pressure, isconnected to one of the two chambers of a Sanborn 267 B/C, differentialtransducer. The other chamber is connected to the oesophageal balloon bymeans of a polyethylene catheter of the same length and characteristicsas the balloon's.

The airflow is measured from the Fleish pneumotachograph by means of aSanborn 270 differential transducer.

The tidal volume is obtained by electronic integration of the flowsignal using an R. C. integrator.

The systemic and pulmonary blood pressures are gauged by means ofSanborn 267 B/C or 1280B pressure transducers.

An electrocardiogram is taken in lead 2. Its use is to monitor a cardiacrate-meter.

All these parameters are recorded on a Sanborn polygraph. Thetranspulmonary pressure and the tidal volume are also displayed asrectangular coordinates on an oscilloscope.

The airways resistance, expressed in cm of water/liter/second, ismeasured by subtracting from the electrical equivalent of thetranspulmonary pressure, a voltage proportional to the flow so as tosynchronise the pressure and volume signals on the oscilloscope [Meadand Whittenberger, J. Appl. Physiol., 5, 779 (1953)].

The value of the pulmonary elastance, expressed in cm of water/liter, isobtained by means of the same principal, i.e., an electrical signalproportioned to the volume is subtracted from the transpulmonarypressure signal, in order to optimize the pressure-flow loop on theoscilloscope.

The details of this method are described by Lulling, et al. [Med.Pharmacol. Exp., 16, 481 (1967)].

The computing operations are carried out with an analogical computerwhich allows the direct reading, cycle to cycle, of the values ofresistance and elastance.

The test compounds are administered by an Aerosol® route. Themicronebulizer of a Bird Mark 7 respirator is fitted on the metalliccannula just after the pneumotachograph. The "puff" of test compound inAerosol® is driven by a 2 kg/cm² pressure allowed to the micronebulizerjust during one inspiration cycle. The micronebulizer is fitted on therespiratory tube only during the "puff". It is weighed just before andjust after administration to determine the amount of test compoundadministered.

When administered by Aerosol® to anesthetized dogs, in whom abronchospasm had been induced by administration of pilocarpine,7-[3-(2-hydroxyethylthio)-2β-(3α-hydroxy-1-octenyl)-5-oxo-1.alpha.-cyclopentyl]-5-heptanoicacid methyl ester at a concentration of 32 mcg/ml caused a 60-65%inhibition of the spasm. The % inhibition of spasms induced bypilocarpine for some of the compounds of this invention is shown belowin Table A.

                                      TABLE A                                     __________________________________________________________________________    Bronchodilator Activity (Pilocarpine Assay) % Inhibition of Spasm                                   % Inhibition of pilocarpine induced                                           spasm as a function of the after drug                                     Dose                                                                              administration                                                            mg/kg                                                                             5 min. 30 min.                                                                           60 min.                                      __________________________________________________________________________    1,9-dioxo-11α,16-dihydroxy-16-methyl-                                   1-hydroxymethyl-5-cis-13-trans                                                prostadiene       3.2 90     90  70                                           1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    1-hydroxymethyl-5-cis-13-trans                                                prostadiene       3.2 80     80  66                                           1,9-dioxo-11α,15-dihydroxy-16,16-                                       trimethylene-1-hydroxymethyl-5-cis-                                           13-trans prostadiene                                                                            3.2 80     74  68                                           1,9-dioxo-15-hydroxy-15-methyl-1-                                             hydroxymethyl-13-trans prostene                                                                 3.2 37     30  30                                           1,9-dioxo-15-hydroxy-1-hydroxy                                                methyl prostane   3.2 70     45  30                                           1,9-dioxo-11α,16-dihyroxy-16-vinyl-                                                       3.2 92     75  55                                           1-acetoxymethyl-5-cis-13-trans                                                prostadiene                                                                   __________________________________________________________________________

The novel compounds of the present invention have utility asbronchodilators.

Bronchodilator activity is determined in guinea pigs againstbronchospasms elicited by intravenous injections of 5-hydroxytryptamine,histamine or acetylcholine by the Konzett procedure. [See J. Lulling, P.Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995(1968)].

EXAMPLE 266 Preparation of trimethylsilyl-2-trimethylsilyloxy acetate

To a solution of 15 g (0.197 mol) of glycolic acid in 50 ml of drypyridine is poured 32.3 g (0.2 mol) of 1,1,1,3,3,3-hexamethyldisilazine.After stirring 15 minutes, 10.86 g (0.1 mol) of trimethylsilyl chlorideis added dropwise. The mixture is stirred for one hour and then filteredfrom a white solid which is washed with petrolium ether. The filtrateand washings are concentrated at reduced pressure at 30° C. The residueis distilled (85°-86°, 15 minutes) to give 38 g of the title compound.

EXAMPLE 267 Preparation of tris-trimethylsilyloxyethylene

To a solution of 50.98 g (0.316 mol) of 1,1,1,3,3,3-hexamethyldisilazinein 250 ml of tetrahydrofuran is added with stirring under argon at 0° C.dropwise 133.3 ml (0.32 mol) of 2.4 M n-butyl lithium in hexane. Afteraddition is completed the solution is maintained at 45° C. for 30minutes. The solution is cooled to -78° and 58.7 g oftrimethylsilyl-2-trimethyl-silyloxy acetate (Example 266) is addeddropwise. After stirring 30 minutes, 43.2 g (0.4 mol) oftrimethylsilylchloride is added over 10 minutes. The solution is allowedto warm to room temperature over 30 minutes. The solvent is removed atreduced pressure. The residue is mixed with an equal volume of petroliumether and filtered from the suspended lithium chloride. The solvent isremoved and the residue is distilled (70°-75° C., 1.4 minute) to give64.65 g of the title compound.

EXAMPLE 268 Preparation of 2-[6-(chloroformyl)hexyl]cyclopent-2-en-1-one

To a suspension of 1.94 g (0.08 mol) of sodium hydride in 100 ml oftetrahydrofuran is added with stirring under argon dropwise a solutionof 17 g (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one in 160 mlof tetrahydrofuran. After the addition is complete, the mixture isstirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 mlof oxalyl chloride is added. The mixture is stirred at 0° C. for 30minutes and at room temperature for 30 minutes. The solution is dilutedwith 500 ml of ether and filtered through Celite. The solvent is removedfrom the filtrate and the residue is extracted with hot hexane twice.The hexane is removed to give 16.0 g of the title compound.

EXAMPLE 269 Preparation of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one

A mixture of 6.3 g of 2-[6-(chloroformyl)hexyl]-cyclopent-2-en-1-one(Example 268) and 16 g of tris-trimethylsilyloxyethylene (Example 267)are stirred at 90° to 100° C. under argon for one hour. To this mixtureis added 25 ml of dioxane and 10 ml of 0.6 N hydrochloric acid. Themixture is heated at 80° C. for 30 minutes. The mixture is poured intobrine and extracted with ether. The ether solution is washed withsaturated sodium bicarbonate and dried over magnesium sulfate. Thesolvent is removed and the residue is chromatographed on a dry column ofsilica gel eluting with ether containing 2% acetic acid to give 1.7 g ofthe title compound (R_(f) =0.45).

EXAMPLE 270 Preparation of2-(6-carbodimethyl-t-butylsilyloxyhex-2-cis-en-yl)-4-dimethyl-t-butylsilyloxy-cyclopent-2-en-1-one

To 5.0 g of 2-(6-carboxyhex-2-cis-enyl)-4-hydroxycyclopent-2-en-1-oneand 7.5 g of imidazole in 24 ml of dimethylformamide is added 10.2 g ofdimethyl-t-butylsilylchloride. The mixture is maintained at 37° C. for 4hours. The mixture is poured into ice water and extracted with hexane.The hexane solution is washed with saturated sodium bicarbonate anddried over magnesium sulfate. The solvent is removed. Toluene is addedand removed. The residue is distilled in a Kugelrohr apparatus (165° C.,0.5-0.1 mm) to give 4.56 g of the title compound.

EXAMPLE 271 Preparation of1-(6-carboxyhex-2-cis-enyl)-4-dimethyl-t-butyl-silyloxycyclopent-2-en-1-on

A solution of1-(6-carbodimethyl-t-butylsilyloxyhex-2-cis-enyl)-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one(Example 270) in 40 ml of acetic acid - tetrahydrofuran - water (4:2:1)is stirred at room temperature for 1.5 hour. The solvents are removed atreduced pressure at 40° C. The residue is dissolved in ether. The ethersolution is washed with water, brine, and dried over magnesium sulfate.The solvent is removed. Toluene is added and removed to give 3.1 g ofthe title compound.

EXAMPLE 272 Preparation of1-[6-(chloroformyl)hex-2-cis-enyl]-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one

To 59.66 g of1-(6-carboxyhex-2-cis-enyl)-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one(Example 271) in 300 ml of tetrahydrofuran containing 0.5 ml ofdimethylformamide at 0° C. under argon with stirring is added over 20minutes 29.2 m of oxalyl chloride in 40 ml of tetrahydrofuran. After 1.5hours the solvent is removed at reduced pressure at 35° C. The residueis dissolved in petrolium ether and filtered through Celite. The solventis removed to give 59.3 g of the title compound.

EXAMPLE 273 Preparation of1-(8-hydroxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one

A mixture of 59.3 g of1-[6-(chloroformyl)hex-2-cis-enyl]-4-dimethyl-t-butylsilyloxycyclopent-2-en-1-one(Example 272) and 101.5 g of tris-trimethylsilyloxyethylene (Example267) is heated under argon at 90°-95° C. for 3 hours 10 minutes. Thereaction mixture is poured into a mixture of 300 ml of tetrahydrofuranand 140 ml of 0.6 N hydrochloric acid and the resulting mixture isstirred at 70° C. for 2.5 hours. The mixture is poured in brine andextracted with ethyl acetate. The organic layer is washed with saturatedsodium bicarbonate and dried of magnesium sulfate. The solvent isremoved and the residue is chromatographed of a dry column of silica geleluting with ethyl acetate. The product bond (R_(f) ≃0.4) is extractedto give 6.45 g of the title compound.

EXAMPLE 274 Preparation of 5-bromopentanoylchloride

To a solution of 97 g of 5-bromopentanoic acid in 240 ml of methylenechloride containing 1 ml of dimethylformamide is added dropwise 76.2 gof oxalyl chloride. The mixture is stirred one hour at room temperatureand 30 minutes at 50° C. The solvent is removed and the residue isdistilled twice (75° C., 0.6 minute) to give 88.2 g of the titlecompound.

EXAMPLE 275 Preparation of 6-bromo-1-hydroxy-2-hexanone

To 191.4 g of tris-trimethylsilyloxyethylene (Example 267) containing 15drops of stannic tetrachloride under argon with stirring at 10° C. isadded 87 g of 5-bromopentanoyl chloride (Example 274) dropwise. Afterone-half of the acid chloride is added, the mixture is stirred until anexotherm ensues. The remaining acid chloride is added dropwisemaintaining the reaction exotherm at 65° C. The mixture is then stirredfor 2.5 hours. The mixture is slowly poured into a stirred mixture of100 ml. of 0.6 N hydrochloric acid and 200 ml of tetrahydrofuran. Themixture is stirred for 30 minutes and poured into brine. The mixture isextracted with ether. The ether solution is washed with saturated sodiumbicarbonate and dried over magnesium sulfate. The solvent is removed.The residue is mixed with petrolium ether and cooled in dry-ice-acetoneto induce crystallization. The petrolium ether is decanted and the solidis dried at reduced pressure to give 64.72 g of the title compound.

EXAMPLE 276 Preparation of 6-bromo-1-dimethyl-t-butylsilyloxy-2-hexanoneethylene ketal

A mixture of 84 g of 6-bromo-1-hydroxy-2-hexanone (Example 275), 240 mlof ethylene glycol, and 1.7 g of p-toluenesulfonic acid is refluxed in1800 ml of toluene using a Dean-Stark trap for 1 hour 45 minutes. Themixtureis cooled to room temperature and washed with saturated sodiumbicarbonate, water, and brine. The solvent is removed giving 75.17 g ofa yellow oil. To a 27.36 g portion of this material and 16.2 g ofimidazole in 57 ml of dimethylformamide at 0° with stirring is added20.55 g of dimethyl-t-butylchlorosilane. The mixture is stirred at roomtemperature for 1.5 hour and then poured into water. The mixture isextracted with petrolium ether. The organic phase is washed with dilutehydrochloric acid, saturated sodium bicarbonate and dried over magnesiumsulfate. The solvent is removed and the residue is distilled in aKlugrohr apparatus (0.5-0.2 mm, 100°-110° C.) to give 35.25 of the titlecompound.

EXAMPLE 277 Preparation of 1-dimethyl-t-butylsilyloxy-2-hexanoneethylene ketal 6-triphenylphosphonium bromide

A mixture of 35.24 g of 6-bromo-1-dimethyl-t-butylsilyloxy-2-hexanoneethylene ketal (Example 276) and 26.2 g of triphenylphosphine in 68 mlof acetonitrile is refluxed 90 hours. The acetonitrile is removed atreduced pressure. The residue is washed three times with ether and driedat reduced pressure to give 53.8 g of the title compound.

EXAMPLE 278 Preparation of2,5-dihydro-2,5-dimethoxy-2-(9-dimethyl-t-butylsilyloxy-8-oxonon-3-cis-enyl)furan

A suspension of 2.3 g (0.096 mol) of oil free sodium hydride is stirredunder argon at 65° C. i 75 ml of dimethylsulfoxide. After gas evolutionceased (1 hour), at 0° C. is added 53.8 g (0.086 mol) of1-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal6-triphenylphosphonium bromide (Example 277) in 160 ml ofdimethylsulfoxide. After stirring 15 minutes at room temperature, 16.3 g(0.087 mol) of 2,5-dihydro-2,5-dimethoxy-2-(3'-oxopropyl)furan [U.S.Pat. No. 3,952,033] in 40 ml of dimethylsulfoxide is added. Afterstirring one hour at room temperature, the solvent is removed at reducedpressure at 55° C. The solid residue is extracted with anether-petrolium ether mixture. The solution is washed with water,saturated sodium bicarbonate and dried over magnesium sulfate. Thesolvent is removed and petrolium ether is added. After standing 30minutes, the triphenylphosphine oxide is removed by filtration. Thesolvent is removed and the residue is chromatographed on a dry column offlorisil eluting first with hexane and then with hexane-ether 5:1 togive 13.2 g of the title compound.

EXAMPLE 279 Preparation of2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one,7-ethylene ketal

A mixture of 66.08 g of2,5-dihydro-2,5-dimethoxy-2-(9-dimethyl-t-butylsilyloxy-8-oxonon-3-cis-enyl)furan(Example 228), 26.4 g of sodium dihydrogen phosphate, 5.2 g of sodiumacetate and 0.5 g of hydroquinone in 1320 ml of dioxane and 660 ml ofwater is stirred at reflux under argon for 22 hours. The mixture iscooled to room temperature, saturated with sodium chloride, and theorganic layer is separated. The aqueous layer is extracted with ether.The combined organic solutions are washed with brine and dried overmagnesium sulfate. The solvent is removed to give 57.5 g of an oil. Tothis is added 300 ml of ether, 300 ml of petrolium ether and 22 g ofanhydrous chloral. The solution is stirred under argon and 23 g oftriethylamine is added. After 1 hour 40 minutes, the solution is washedwith water, dilute hydrochloric acid, saturated sodium bicarbonate,brine, and dried over magnesium sulfate. The solvent is removed and theresidue is chromatographed on a dry column of silica gel eluting withethylacetate-hexane 1:1 to give 14.55 g of the title compound (R_(f)=0.4).

EXAMPLE 280 Preparation of2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one,7-ethylene ketal

A mixture of 14.5 g (0.0367 mol) of2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one,7-ethylene ketal (Example 279) and 3.34 g (0.04 mol) of imidazole in 30ml of dimethylformamide is stirred as 4.98 g (0.046 mol) oftrimethylsilylchloride is added. After one hour, the mixture is pouredinto water and extracted with hexane. The hexane solution is washed withwater, saturated sodium bicarbonate, and dried over magnesium sulfate.The solution is filtered through a pad of silica gel. The solvent isremoved and the residue is dried at reduced pressure to give 12.5 g ofthe title compound.

EXAMPLE 281 Preparation of2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-cis-enyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-one

A mixture of2-(8-hydroxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one(Example 273), 14 ml of 2-methoxy propene, and 0.23 g of ammoniumnitrate in 35 ml of benzene is added 7 ml of dimethoxypropane.P-toluenesulfonic acid is added in very small portions until TLCindicates the reaction is initiated. The mixture is stirred 1.5 hour atroom temperature, 40° C. for 15 minutes, and another 30 minutes at roomtemperature. To the stirred solution is added 50 g of crushed 4Amolecular sieve. After 15 minutes, the solution is filter washed withsaturated sodium bicarbonate, and dried over sodium sulfate. The solventis removed and the residue is chromatographed on a dry column of silicagel eluting with ether-hexane 1:1. The product bond (R_(f) ≃0.5) isextracted to give 3.44 g of the title compound.

EXAMPLE 282 Preparation of2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one, 7-ethylene ketal

A solution of 5.5 g of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one(Example 269), 25 ml of ethylene glycol, and 0.1 g of p-toluenesulfonicacid in 200 ml of toluene is refluxed for 40 minutes using a Dean-Starktrap. The solution is poured into saturated sodium bicarbonate. Themixture is extracted wth benzene. The organic solution is washed threetimes with water and dried over magnesium sulfate. The solvent isremoved to give 6.0 g of the title compound.

EXAMPLE 283 Preparation of2-(8-trimethylsilyloxy-7-oxo-octyl)cyclopent-2-en-1-one,7-ethylene ketal

To a solution of 2.2 g of2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one,7-ethylene ketal (Example232) in 20 ml of pyridine is added 4.6 ml of1,1,1,3,3,3-hexamethyldisilazine and, dropwise, 2.3 ml oftrimethylsilylchloride. After 15 minutes, the excess reagents andsolvent is removed at reduced pressure. The residue is taken up in etherand filtered through a short pad of silica gel. The solvent is removed.Toluene is added and removed. The residue is dried at reduced pressureto give 2.77 g of the title compound.

EXAMPLES 284-294

By the sequence of reactions described hereinabove for Examples 268 and269 or 270 to 273 and the protection reaction described hereinabove inExample 281, the protected cyclopent-2-en-1-ones listed in Table 28hereinbelow are prepared from the indicated carboxylic acids.

                                      TABLE 28                                    __________________________________________________________________________    Example                                                                            Carboxylic acid                                                                              Protected cyclopent-2-en-1-one                            __________________________________________________________________________    284  2-(6-carboxyhexyl) cyclopent-                                                                2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               2-en-1-one     hexylcyclopent-2-en-1-one                                 285  2-(5-carboxypentyl) cyclopent-                                                               2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               2-en-1-one     pentylcyclopent-2-en-1-one                                286  2-(7-carboxyheptyl) cyclopent-                                                               2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               2-en-1-one     heptycyclopent-2-en-1-one                                 287  2-(6-carboxyhex-2-cis-enyl)-                                                                 2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               cyclopent-2-en-1-one                                                                         hex-2-cis-enyl]cyclopent-2-en-1-one                       288  2-(5-carboxypent-2-cis-enyl)-                                                                2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               cyclopent-2-en-1-one                                                                         pent-2-cis-enyl]cyclopent-2-en-1-one                      289  2-(7-carboxyhept-2-cis-enyl)-                                                                2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               cyclopent-2-en-1-one                                                                         hept-2-cis-enyl]cyclopent-2-en-1-one                      290  2-(5-carboxypent-2-cis-enyl)-                                                                2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               4-hydroxycyclopent-2-en-1-                                                                   pent-2-cis-enyl]4-(2-methoxypropyl-2-oxy) cyclo-               one            pent-2-en-1-one                                           291  2-(7-carboxyhept-2-cis-enyl)-                                                                2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               4-hydroxycyclopent-2-en-1-                                                                   hept-2-cis-enyl]4-(2-methoxypropyl-2-oxy) cyclo-               one            pent-2-en-1-one                                           292  2-(6-carboxyhexyl)-4-hydroxy-                                                                2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               cyclopent-2-en-1-one                                                                         hexyl]-4-(2-methoxypropyl-2-oxy) cyclopent-2-en-1-                            one                                                       293  2-(5-carboxypentyl)-4-hydroxy-                                                               2-[5-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               cyclopent-2-en-1-one                                                                         pentyl]-4-(2-methoxypropyl-2-oxy) cyclopent-2-en-                             1-one                                                     294  2-(7-carboxyheptyl)-4-hydroxy-                                                               2-[7-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-               cyclopent-2-en-1-one                                                                         heptyl]-4-(2-methoxypropyl-2-oxy) cyclopent-2-en-                             1-one                                                     295  2-(6-carboxyhex-2-cis-enyl)-                                                                 2-[6)4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)-                4(R)-hydroxycyclopent-2-en                                                                   hex-2-cis-enyl] -4(R)-2-methoxypropyl-2-oxy) cyclo-            1-one          pent-2-en-1-one                                           296  2-(6-carboxyhexyl)-4(R)-hy-                                                                  2-[6-(4-methoxy-2,2-diemthyl-1,3-dioxolan-4-yl)-               droxycyclopent-2-en-1-one                                                                    hexyl] -4(R)-(2-methoxypropyl-2-oxy) cyclopent-2-en-                          1-one                                                     __________________________________________________________________________

EXAMPLES 297-298

By the sequence of reaction given hereinabove in the Examples 274 to280, the protected cyclopent-2-en-1-ones of Table 29 are prepared fromindicated Bromocarboxylic acid.

                                      TABLE 29                                    __________________________________________________________________________     Example                                                                           Bromo-carboxylic acid                                                                      Protected Cyclopent-2-en-1-one                              __________________________________________________________________________    297  4-bromobutanoyl-chloride                                                                   1-(7-dimethyl-t-butylsilyloxy-6-oxohept-2-                                    cis-enyl)-4-trimethylsilyloxycyclopent-2-en-                                  1-one,6-ethylene ketal                                      298  6-bromohexanoyl chloride                                                                   1-(9-dimethyl-t-butylsilyloxy-8-oxonon-2-cis-                                 enyl)-4-trimethylsilyloxycyclopent-2-en-1-                                    one,8-ethylene ketal                                        __________________________________________________________________________

EXAMPLES 299-306

By the methods described hereinabove in Examples 268 and 269 and theketalization reaction described in Example 282, thecyclopent-2-en-1-ones in Table 30 are prepared from the indicatedcarboxylic acid. By the methods described hereinabove in the sequence ofreactions shown in Examples 270-273 and the ketalization reactiondescribed in Example 282 the 4-hydroxy-cyclopent-2-en-1-ones in Table 30are prepared from the indicated carboxylic acid.

                                      TABLE 30                                    __________________________________________________________________________    Example                                                                            Carboxylic acid     Cyclopent-2-en-1-one                                 __________________________________________________________________________    299  2-(5-carboxypentyl) cyclopent-2-en-1-one                                                          2-(7-hydroxy-6-oxoheptyl) cylopent-2-en-1-one,-                               6-ethylene ketal                                     300  2-(7-carboxyheptyl) cyclopent-2-en-1-one                                                          2-(9-hydroxy-8-oxononyl) cyclopent-2-en-1-one,-                               8-ethylene ketal                                     301  2-(6-carboxyhexyl)-4-hydroxycyclopent-2-                                                          2-(8-hydroxy-7-oxooctyl)-4-hydroxycyclopent-2-            en-1-one            en-1-one, 7-ethylene ketal                           302  2-(5-carboxypentyl)-4-hydroxycyclopent-2-                                                         2-(7-hydroxy-6-oxoheptyl)-4-hydroxycyclopent-2-           en-1-one            en-1-one, 6-ethylene ketal                           303  2-(7-carboxyheptyl) cyclopent-2-en-1-one                                                          2-(9-hydroxy-8-oxononyl)-4-hydroxycyclopent-2-                                en-1-one, 8-ethylene ketal                           304  2-(6-carboxyhex-2-cis-enyl) cyclopent-2-                                                          2-(8-hydroxy-7-oxooct-2-cis-enyl) cyclopent-2-            en-1-one            en-1-one, 7-ethylene ketal                           305  2-(5-carboxypent-2-cis-enyl) cyclopent-2-                                                         2-(7-hydroxy-6-oxohept-2-cis-enyl) cyclopent-2-           en-1-one            en-1-one, 6-ethylene ketal                           306  2-(7-carboxyhept-2-cis-enyl) cyclopent-2-                                                         2-(9-hydroxy-8-oxonon-2-cis-enyl) cyclopent-2-            en-1-one            en-1-one, 8-ethylene ketal                           307  2-(6-carboxyhex-2-cis-enyl)-4(R)-hy-                                                              2-(8-hydroxy-7-oxoct-2-cis-enyl)-4(R)-hydroxy-            droxycyclopent-2-en-1-one                                                                         cyclopent-2-en-1-one, 7-ethylene ketal               308  2-(6-carboxyhexyl)-4(R)-hydroxycyclo-                                                             2-(8-hydroxy-7-oxooctyl)-4(R)-hydroxycyclopent-           pent-2-en-1-one     2-en-1-one, 7-ethylene ketal                         __________________________________________________________________________

EXAMPLE 309 Preparation of2-(8-trimethylsilyloxy-7-oxooctyl)-4-trimethylsilyloxycyclopent-2-en-1-one,7-ethyleneketal

To a solution of 2.2 g of2-(8-hydroxy-7-oxooctyl)-4-hydroxycyclopent-2-en-1-one,7-ethylene ketal(Example 301) in 40 ml of pyridine is added 9.2 ml1,1,1,3,3,3-hexamethyldisilazine and, dropwise, 4.6 ml oftrimethylsilylchloride. After 30 minutes, the excess reagents andpyridine are removed at reduced pressure. The residue is taken up inether and filtered through a short pad of silica gel. The solvent isremoved and the residue is dried at reduced pressure to give the titlecompound.

EXAMPLES 310-318

By the methods described hereinabove in Examples 283 and 309, thehydroxycyclopent-2-en-1-ones listed in Table 31 are converted to theirtrimethylsilyl ethers shown.

                                      TABLE 31                                    __________________________________________________________________________    Example                                                                             Hydroxycyclopent-2-en-1-one of Example                                                           Protected cyclopent-2-en-1-one                       __________________________________________________________________________    310  299                 2-(7-trimethylsilyloxy-6-oxoheptyl) cyclopent-                                2-en-1-one, 6-ethylene ketal                         311  300                 2-(9-trimethylsilyloxy-8-oxonyl) cyclopent-2-                                 en-1-one, 8-ethylene ketal                           312  302                 2-(7-trimethylsilyloxy-6-oxoheptyl)-4-trimeth-                                ylsilyloxycyclopent-2-en-1-one, 6-ethylene                                    ketal                                                313  303                 2-(9-trimethylsilyloxy-8-oxononyl)-4-trimeth-                                 ylsilyloxycyclopent-2-en-1-one, 8-ethylene                                    ketal                                                314  304                 2-(8-trimethylsilyloxy-7-oxooct-2-cis-enyl)-                                  cyclopent-2-en-1-one, 7-ethylene ketal               315  305                 2-(7-trimethylsilyloxy-6-oxohept-2-cis-enyl)-                                 cyclopent-2-en-1-one, 6-ethylene ketal               316  306                 2-(9-trimethylsilyloxy-8-oxonon-2-cis-enyl)-                                  cyclopent-2-en-1-one, 8-ethylene ketal               317  307                 2-(8-trimethylsilyloxy-7-oxooct-2-cis-enyl)-                                  4(R)-trimethylsilyloxycyclopent-2-en-1-one, 7-                                ethylene ketal                                       318  308                 2-(8-trimethylsilyloxy-7-oxooctyl)-4(R)-tri-                                  methylsilyloxycyclopent-2-en-1-one, 7-ethylene                                ketal                                                __________________________________________________________________________

EXAMPLE 319 Preparation of1,9-dioxo-11α,15-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadieneand1,9-dioxo-11α,15-epi-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene

To a solution of 1.95 g (0.00533 mol) of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-trans-octene (Example 13)in 6.5 ml of ether is added at -78° C. with stirring under argon 6.66 ml(0.0107 mol) of 1.6M t-butyllithium in pentane. After 15 minutes at -78°C., the mixture is stirred at -10° to -5° C. for 90 minutes. Thesolution is cooled to -78° C. and a solution of 0.704 g (0.00533 mol) ofcopper pentyne and 1.75 g (0.0106 mol) of hexamethylphosphoroustriamidein 20 ml of ether is added. After stirring for one hour, 1.7 g (0.0044mol) of2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolon-4-yl)hex-2-cis-enyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-one(Example 281) in 13 ml of ether is added. The solution is maintained at-40° to -50° C. for one hour and -30° C. for 30 minutes. A solution of 1ml of acetic acid in 5 ml of ether is added followed by a saturatedsolution of ammonium chloride and dilute hydrochloric acid. The solutionis filtered and solids are washed with ether. The combined filtrate isextracted with ether. The ether solution is washed with saturated sodiumbicarbonate and dried over magnesium sulfate. The ether is removedgiving a yellow oil which is dissolved in 60 ml of aceticacid-tetrahydrofuran-water 4:2:1 and heated to 40°-50° C. for 70minutes. The solvent is removed at reduced pressure at 50° C. Theresidue is dissolved in ethyl acetate. The ethyl acetate solution iswashed with saturated sodium bicarbonate, brine, and dried overmagnesium sulfate. The solvent is removed. The residue ischromatographed on a dry column of silica gel eluting with ethylacetate-benzene 3:2 containing 1% acetic acid to give 0.35 g of 1,9-dioxo-11α,15-dihydroxy-1-hydroxy-methyl-16,16-trimethylene-13-trans-5-cis-prostadieneand 0.39 g of1,9-dioxo-11α,15-epi-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene.

EXAMPLE 320 Preparation of1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis-13-trans-prostadiene

To a solution of 2.9 g (5.6 mmol) of (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-butylstannyloctene (Example 210a) in4 ml of tetrahydrofuran at -78° C. under argon with stirring is added2.4 ml of 2.4M n-butyllithium in hexane. The solution is stirred at -30°to -20° C. for 2 hours. A solution of 0.74 g (5.6 mmol) of copperpentyne and 2.3 ml of hexamethylphosphoroustriamide in 18 ml of ether isadded at -78° C. The solution is stirred at -78° C. for 1.5 hour. Asolution of 2.0 g (5.2 mmol) of2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-cis-enyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-one(Example 281) in 20 ml of ether is added. The solution is stirred at-30° to -20° C. for 1.5 hour. To the solution is added 100 ml ofsaturated ammonium chloride. The mixture is extracted with ether and theether solution is washed with dilute hydrochloric acid, saturated sodiumbicarbonate, and dried over magnesium sulfate. The solvent is removedand the residue is dissolved in 90 ml of aceticacid-tetrahydrofuran-water 4:2:1. The solution is stirred at roomtemperature for 2 hours. The solvents are removed at reduced pressure at50° C. Toluene was added and removed. The residue is chromatographed ona dry column of silica gel eluting with ethyl acetate to give 0.5 g ofthe title compound.

EXAMPLES 321-422

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 32 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one. In thosecases where isomers are obtained at the C₁₅ or C₁₆ position, only theC₁₅ or C₁₆ -normal isomers are listed in Table 32; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomers are alsoformed and are part of this invention.

In those cases where the initial conjugate addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 32                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example    1,9-dioxo-1-hydroxymethylprostene            __________________________________________________________________________    321  319   281        49         1,9-dioxo-11α,15-dihydroxy-1-hydrox                                     y-                                                                            methyl-16,16-trimethylene-20-nor-5-                                           cis-13-trans-prostadiene                     322  319   281        50         1,9-dioxo-11α,15-dihydroxy-1-hydrox                                     y-                                                                            methyl-16,16-trimethylene-20-methyl-5-                                        cis-13-trans-prostadiene                     333  319   281        51         1,9-dioxo-11α,15-dihydroxy-1-hydrox                                     y-                                                                            methyl-16,16-trimethylene-20-ethyl-5-                                         cis-13-trans-prostadiene                     334  320   281        199        1,9-dioxo-11α,16-dihydroxy-16-cyclo                                     -                                                                             propyl-20-ethyl-1-hydroxymethyl-5-cis-                                        13-trans-prostadiene                         335  320   281        201        1,9-dioxo-11α,16-dihydroxy-16-vinyl                                     -20-                                                                          ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  336a 320   281        198        1,9-dioxo-11α,16-dihydroxy-16-cyclo                                     -                                                                             propyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  336b 320   281        210c       1,9-dioxo-11α,16-dihydroxy-16-ethyl                                     -1-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                          337  319   281        74         dl-erythro-1,9-dioxo-11α,15-dihydro                                     xy-                                                                           16-methoxy-1-hydroxymethyl-5-cis-13-                                          trans-prostadiene                            338  319   281        77         dl-erythro-1,9-dioxo-11α                                                ,15-dihydroxy-                                                                16-ethoxy-1-hydroxymethyl-5-cis-13-                                           trans-prostadiene                            339  319   281        83         dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-1-hydroxymethyl-20-nor-5-cis-13-                                        trans-prostadiene                            340  319   281        84         dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-1-hydroxymethyl-20-methyl-5-cis-                                        13-trans-prostadiene                         341  319   281        85         dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-1-hydroxymethyl-20-ethyl-5-cis-                                         13-trans-prostadiene                         342  319   281        86         dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-19-methyl-1-hydroxymethyl-5-cis-                                        13-trans-prostadiene                         343  319   281        87         dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-1-hydroxymethyl-5-cis-13-trans-                                         17-trans-prostatriene                        344  319   281        69         d1-threo-1,9-dioxo-11α,15,16-trihy-                                     droxy-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  345  319   281        88         dl-threo-1,9-dioxo-11α,15,16-trihy-                                     droxy-20-nor-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene                            346  319   281        76         dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  347  319   281        89         dl-threo-1,9-dioxo-11α,15,16-trihy-                                     droxy-20-methyl-1-hydroxymethyl-5-cis-                                        13-trans-prostadiene                         348  319   281        90         dl-threo-1,9-dioxo-11α,15,16-trihy-                                     droxy-20-ethyl-1-hydroxymethyl-5-cis-                                         13-trans-prostadiene                         349  319   281        91         dl-threo-1,9-dioxo-11α,15,16-trihy-                                     droxy-19-methyl-1-hydroxymethyl-5-cis-                                        13-trans-prostadiene                         350  319   281        92         dl-threo-1,9-dioxo-11α,15,16-trihy-                                     droxy-1-hydroxymethyl-5-cis-13-trans-                                         17-trans-prostatriene                        351  319   281        107        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-5-cis-13-trans-prostadiene            352  319   281        108        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-19,20-dinor-5-cis-13-trans-                                            prostadiene                                  353  319   281        109        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-18,19,20-trinor-5-cis-13-trans-                                        prostadiene                                  354  319   281        110        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-20-nor-5-cis-13-trans-prosta                                           diene                                        355  319   281        144        1,9-dioxo-11α,16-dihydroxy-17-methy                                     l-                                                                            1-hydroxymethyl-5-cis-13-trans-prosta-                                        diene                                        356  319   281        112        1,9-dioxo-11α,16-dihydroxy-20-methy                                     l-                                                                            1-hydroxymethyl-5-cis-13-trans-prosta-                                        diene                                        357  319   281        113        1,9-dioxo-11α,16-dihydroxy-20-ethyl                                     -1-                                                                           hydroxymethyl-5-cis-13-trans-prosta-                                          diene                                        358  319   281        139a       1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-                                                                            20-ethyl-1-hydroxymethyl-5-cis-13-                                            trans-prostadiene                            359  319   281        115        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-13-trans-17-cis-5-cis-prostatri-                                       ene                                          360  319   281        135        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-1-                                                                          hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                          361  319   281        136        1,9-dioxo-11α,16-dihydroxy-17,17,20                                     -                                                                             trimethyl-1-hydroxymethyl-5-cis-13-                                           trans-prostadiene                            362  319   281        137        1,9-dioxo-11α,16-dihydroxy-16,20-di                                     meth-                                                                         yl-1-hydroxymethyl-13-trans-5-cis-pro-                                        stadiene                                     363  319   281        138        1,9-dioxo-11α,16-dihydroxy-17,17-di                                     -                                                                             methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  364  319   281        139        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-                                                                            1-hydroxymethyl-13-trans-17-trans-5-                                          cis-prostatriene                             365  319   281        149        1,9-dioxo-11α,16-dihydroxy-20-methy                                     l-                                                                            1-hydroxymethyl-13-trans-17-trans-5-                                          cis-prostatriene                             366  319   281        150        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-                                                                            1-hydroxymethyl-5-cis-13-trans-prosta-                                        diene                                        367  319   281        151        1,9-dioxo-11α,16-dihydroxy-17,20-di                                     -                                                                             methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  368  319   281        152        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-13-trans-17-trans-5-cis-prosta-                                        triene                                       369  319   281        153        1,9-dioxo-11α ,16(R)-dihydroxy-1-hy                                     droxy-                                                                        methyl-5-cis-13-trans-prostadiene            370  319   281        154        1,9-dioxo-11α ,16(S)-dihydroxy-1-hy                                     droxy-                                                                        methyl-5-cis-13-trans-prostadiene            371  319   281        148a       1,9-dioxo-11α,16-dihydroxy-20-ethyl                                     -1-                                                                           hydroxymethyl-5-cis-13-trans-17-trans-                                        prostatriene                                 372  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     -hydroxy-                                                          phenylmethoxy-1-                                                                         methyl-5-cis-13-trans-prostadiene                                  trans-octene (U.                                                              S. Pat. No.                                                                   3,873,607).                                             373  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-2                                     0-methyl-                                                          phenylmethoxy-                                                                           1-hydroxymethyl-5-cis-13-trans-prosta-                             1-trans-nonene                                                                           diene                                                              (U.S. Pat. No.                                                                3,873,607).                                             374  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydoxy-20                                     -ethyl-1-                                                          phenylmethoxy-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                             1-trans-decene                                                                           ene                                                                (U.S. Pat. No.                                                                3,873,607).                                             375  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     6,16-di-                                                           phenylmethoxy-                                                                           methyl-1-hydroxymethyl-5-cis-13-trans-                             4,4-dimethyl-                                                                            prostadiene                                                        1-trans-octene                                                                (U.S. Pat. No.                                                                3,873,607).                                             376  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     7,17-di-                                                           phenylmethoxy-                                                                           methyl-1-hydroxymethyl-5-cis-13-trans-                             5,5-dimethyl-                                                                            prostadiene                                                        1-trans-octene                                                                (U.S. Pat. No.                                                                3,873,607).                                             377  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     6-methyl-                                                          phenylmethoxy-                                                                           1-hydroxymethyl-5-cis-13-trans-prosta-                             4-methyl-1-                                                                              diene                                                              trans-octene                                                                  (U.S. Pat. No.                                                                3,876,690).                                             378  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     6-ethyl-                                                           phenylmethoxy-                                                                           1-hydroxymethyl-5-cis-13-trans-prosta-                             4-ethyl-1-trans-                                                                         diene                                                              octene (U.S.                                                                  Pat. No.                                                                      3,876,690).                                             379  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     7,20-                                                              phenylmethoxy-4-                                                                         tetra-nor-16-cyclopentyl-1-hydroxy-                                cyclopentyl-1-                                                                           methyl-5-cis-13-trans-prostadiene                                  trans-butene-                                                                 (U.S. Pat. No.                                                                3,884,969).                                             380  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     6,20-                                                              phenylmethoxy-3-                                                                         pentanor-15-cyclohexyl-1-hydroxymethyl-                            cyclohexyl-1-                                                                            5-cis-13-trans-prostadiene                                         trans-pentene                                                                 (U.S. Pat. No.                                                                3,884,969).                                             381  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     8,20-tri-                                                          phenylmethoxy-                                                                           nor-17-cyclohexyl-1-hydroxymethyl-5-cis-                           5-cyclohexyl-1-                                                                          13-trans-prostadiene                                               trans-pentene                                                                 (U.S. Pat. No.                                                                3,884,969).                                             382  319   281        1-iodo-3-tri-                                                                            1,9-dioxo-11α,15α-dihydroxy-1                                     9,20-dinor-                                                        phenylmethoxy-6-                                                                         18-cyclopentyl-1-hydroxymethyl-5-cis-                              cyclopentyl-1-                                                                           13-trans-prostadiene                                               trans-hexene                                                                  (U.S. Pat. No.                                                                3,884,969).                                             383  319   281        1-iodo-3-methyl-                                                                         1,9-dioxo-11α,15α-dihydroxy-1                                     5-methyl-                                                          3-trimethylsilyl-                                                                        1-hydroxymethyl-5-cis-13-trans-prosta-                             oxy-trans-1-octene                                                                       diene                                                              (Example 125)                                           384  319   281        1-iodo-3-methyl-                                                                         1,9-dioxo-11α,15α-dihydroxy-1                                     5-methyl-                                                          3-trimethylsilyl-                                                                        20-ethyl-1-hydroxymethyl-5-cis-13-                                 oxy-trans-1-decene                                                                       trans-prostadiene                                                  (Example 190a)                                          385  320   281        159        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-p-fluorophenoxy-1-                                             hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                          386  320   281        186        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-phenoxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene                   387  320   281        181        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-p-bromophenoxy-1-hydroxy-                                      methyl-5-cis-13-trans-prostadiene            388  320   281        182        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-p-t-butylphenoxy-1-hy-                                         droxymethyl-5-cis-13-trans-prostadiene       389  320   281        183        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-p-methoxyphenoxy-1-hy-                                         droxymethyl-5-cis-13-trans-prostadiene       390  320   281        184        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-m-chlorophenoxy-1-hy-                                          droxymethyl-5-cis-13-trans-prostadiene       391  320   281        180        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-m-trifluorophenoxy-1-hy-                                       droxymethyl-5-cis-13-trans-prostadiene       392  320   281        185        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,-                                                                     20-tetranor-16-(3,4-dichlorophenoxy)-                                         1-hydroxymethyl-5-cis-13-trans-prosta-                                        diene                                        393  320   281        186b       1,9-dioxo-11α,15α-dihydroxy-1                                     8,19,20-                                                                      trinor-17-phenyl-hydroxymethyl-5-                                             cis-13-trans-prostadiene                     394  320   281        186e       1,9-dioxo-11α,15α-dihydroxy-1                                     8,19,20-                                                                      trinor-17-(m-trifluoromethylphenyl)-1-                                        hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                          395  320   281        186d       1,9-dioxo-11α,15α-dihydroxy-1                                     8,19,20-                                                                      trinor-17-(p-methoxyphenyl)-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene            396  319   290        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihyroxy-1-                                     hydroxy-                                                           ylmethoxy-1-trans-                                                                       methyl-2-nor-5-cis-13-trans-prostadiene                            octene (U.S. Pat. No.                                                         3,873,607)                                              397  319   290        190        1,9-dioxo-11α,15α-dihydroxy-1                                     5-methyl-                                                                     1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene                                  398  319   290        1-iodo-3-triphen-                                                                        1,9-dioxo-11α,15α-dihydroxy-1                                     6,16-di-                                                           ylmethoxy-5,5-di-                                                                        methyl-1-hydroxymethyl-2-nor-5-cis-13-                             methyl octene (U.S.                                                                      trans-prostadiene                                                  Pat. No. 3,873,607                                      399  319   290        13         1,9-dioxo-11α,15α-dihydroxy-1                                     6,16-tri-                                                                     methylene-1-hydroxymethyl-2-nor-5-cis-                                        13-trans-prostadiene                         400  319   290        76         erythro-1,9-dioxo-11α,15α,16-                                     trihydroxy-                                                                   1-hyroxymethyl-2-nor-5-cis-13-trans-                                          prostadiene                                  401  319   290        69         threo-1,9-dioxo-11α,15α,16-tr                                     ihydroxy-                                                                     1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene                                  402  319   290        74         erythro-1,9-dioxo-11α,15α-dih                                     ydroxy-16-                                                                    methoxy-1-hydroxymethyl-2-nor-5-cis-13-                                       trans-prostadiene                            403  319   290        107        1,9-dioxo-11α,16-dihydroxy-1-hydrox                                     y-                                                                            methyl-2-nor-5-cis-13-trans-prostadiene      404  319   290        130        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-1-                                                                          hydroxymethyl-2-nor-5-cis-13-trans-                                           prostadiene                                  405  319   290        134        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-                                                                            1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene                                  406  320   290        186        1,9-dioxo-11α,15α                                                 -dihydroxy-2,17,18,-                                                          19,20-pentanor-16-phenoxy-1-hydroxy-                                          methyl-5-cis-13-trans-prostadiene            407  320   290        180        1,9-dioxo-11α,15α-dihydroxy-2                                     ,17,18,-                                                                      19,20-pentanor-16-m-trifluoromethyl-                                          phenoxy-1-hydroxymethyl-5-cis-13-trans-                                       prostadiene                                  408  319   290        194        1,9-dioxo-11α,16-dihydroxy-16-vinyl                                     -1-                                                                           hydroxymethyl-2-nor-5-cis-13-trans-                                           prostadiene                                  409  320   290        198        1,9-dioxo-11α,16-dihydroxy-16-cyclo                                     pro-                                                                          pyl-1-hydroxymethyl-2-nor-5-cis-13-                                           trans-prostadiene                            410  320   290        186b       1,9-dioxo-11α,15α-dihydroxy-2                                     ,18,19,-                                                                      20-tetranor-17-phenyl-1-hydroxymethyl-                                        5-cis-13-trans-prostadiene                   411  319   290        186e       1,9-dioxo-11α,15α-dihydroxy-2                                     ,18,19,-                                                                      20-tetranor-17-(m-trifluorophenyl)-1-                                         hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                          412  319   290        186d       1,9-dioxo-11α,15α-dihydroxy-2                                     ,18,19,-                                                                      20-tetranor-17-(p-methoxyphenyl)-1-                                           hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                          413  319   285        125        1,9-dioxo-15-hydroxy-15-methyl-1-hy-                                          droxymethyl-2-nor-13-trans-prostene          414  319   289        130        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-                                                                            1-homo-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  415  319   289        134        1,9-dioxo-11α,16-dihydroxy-16-methy                                     l-                                                                            1-homo-1-hydroxymethyl-5-cis-13-trans-                                        17-trans-prostatriene                        416  320   289        186        1,9-dioxo-11α,15α-dihydroxy-1                                     -homo-17,-                                                                    18,19,20-tetranor-16-phenoxy-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene            417  320   289        180        1,9-dioxo-11α,15α-dihyroxy-1-                                     homo-17,-                                                                     18,19,20-tetranor-16-m-trifluoromethyl-                                       phenoxy-1-hydroxymethyl-5-cis-13-trans-                                       prostadiene                                  418  319   289        194        1,9-dioxo-11α,16-dihydroxy-16-vinyl                                     -1-                                                                           homo-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene                                  419  320   289        198        1,9-dioxo-11α,16-dihydroxy-16-cyclo                                     -                                                                             propyl-1-homo-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene                            420  320   289        186b       1,9-dioxo-11α,15α-dihydroxy-1                                     -homo-18,-                                                                    19,20-trinor-17-phenyl-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene                   421  319   289        186e       1,9-dioxo-11α,15α-dihydroxy-1                                     -homo-18,-                                                                    19,20-trinor-17-(m-trifluorophenyl)-13-                                       trans-1-hydroxymethyl-5-cis-prostadiene      422  319   289        186d       1,9-dioxo-11α,15α-dihydroxy-1                                     -homo-18,-                                                                    19,20-trinor-17-(p-methoxyphenyl)-13-                                         trans-1-hydroxymethyl-5-cis-prostadiene      __________________________________________________________________________

EXAMPLES 423-445

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 33 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table33. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymmetric carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 33                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-1-hydroxymethylprostene and           Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    423  319   281        246     nat(and ent)-1,9-dioxo-11α,15-dihydrox                                  y-                                                                            15,16-tetramethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-5-cis,13-trans-                                           prostadiene                                     424  320   281        245     nat(and ent)-1,9-dioxo-11α,16-dihydrox                                  y-                                                                            16,17-tetramethylene-18,19,20-trinor-1-                                       hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                             425  319   281        243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                  hydroxymethyl-5-cis-13-trans-prostadi-                                        ene                                             426  319   281        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  hydroxymethyl-13-trans-5-cis-prostadiene        427  319   281        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  N                                                                             hydroxymethyl-13-trans-5-cis-prostadiene        428  319   281        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-trimethylene-17,18,19,20-tetranor-                                      1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             429  320   281        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-pentamethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-5-cis-                                           prostadiene                                     430  319   281        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-dimethylene-1-                                   hydroxymethyl-13-trans-5-cis-prostadiene        431  319   281        250     nat-15S,17S-(and ent-15R,17R)-1,9,-dioxo-                                     11α,15-dihydroxy-15,17-dimethylene-1-h                                  y-                                                                            droxymethyl-13-trans-5-cis-prostadiene          432  319   281        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-tetramethylene-                                  1-                                                                            hydroxymethyl-13-trans-5-cis-prostadiene        433  319   281        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-tetramethylene-                                  1-                                                                            hydroxymethyl-13-trans-5-cis-prostadiene        434  320   281        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene                                     435  320   281        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene                                     436  319   281        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             437  319   281        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             438  320   281        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             439  320   281        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             440  319   281        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene                                     441  319   281        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene                                     442  320   281        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-5-cis-                                        prostadiene                                     443  320   281        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-5-cis-                                        prostadiene                                     444  320   281        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-5-cis-                                           prostadiene                                     445  320   281        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-5-cis-                                           prostadiene                                     __________________________________________________________________________

EXAMPLES 446-530

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 34 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers is listed in Table 34; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomers are alsoformed and are part of this invention.

In those cases where the initial conjugate addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 34                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example   1,9-dioxo-1-hydroxymethylprostene             __________________________________________________________________________    446  319   292         49       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-nor-13-trans-                                        prostene                                      447  319   292         50       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-methyl-13-trans-                                     prostene                                      448  319   292         51       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-ethyl-13-trans-                                      prostene                                      449  320   292        193       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    ro-                                                                           pyl-20-ethyl-1-hydroxymethyl-13-trans-                                        prostene                                      450  320   292        195       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    20-                                                                           ethyl-1-hydroxymethyl-13-trans-prostene       451  320   292        192       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    ro-                                                                           pyl-1-hydroxymethyl-13-trans-prostene         452  319   292         13       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-13-trans-prostene       453  320   292        210a      1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16-vinyl-13-trans-prostene                 454  319   292         74       dl-erythro-1,9-dioxo-11α,15-dihydrox                                    y-16-                                                                         methoxy-1-hydroxymethyl-13-trans-prost-                                       ene                                            455a                                                                              319   292         77       dl-erythro-1,9-dioxo-11α,15-dihydrox                                    y-16-                                                                         ethoxy-1-hydroxymethyl-13-trans-prostene       455b                                                                              320   292        210c      1,9-dioxo-11α,16-dihydroxy-16-ethyl-                                    1-hy-                                                                         droxymethyl-13-trans-prostene                 456  319   292         83       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    -                                                                             droxy-1-hydroxymethyl-20-nor-13-trans-                                        prostene                                      457  319   292         84       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    -                                                                             droxy-1-hydroxymethyl-20-methyl-13-trans-                                     prostene                                      458  319   292         85       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    -                                                                             droxy-20-ethyl-1-hydroxymethyl-13-trans-                                      prostene                                      459  319   292         86       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    -                                                                             droxy-19-methyl-1-hydroxymethyl-13-trans-                                     prostene                                      460  319   292         87       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    -                                                                             droxy-1-hydroxymethyl-13-trans-17-trans-                                      prostadiene                                   461  319   292         69       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          1-hydroxymethyl-13-trans-prostene             462  319   292         88       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-nor-1-hydroxymethyl-13-trans-prostene      463  319   292         76       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    -                                                                             droxy-1-hydroxymethyl-13-trans-prostene       464  319   292         89       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-methyl-1-hydroxymethyl-13-trans-pro-                                       stene                                         465  319   292         90       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-ethyl-1-hydroxymethyl-13-trans-prost-                                      ene                                           466  319   292         91       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          19-methyl-1-hydroxymethyl-13-trans-pro-                                       stene                                         467  319   292         92       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          1-hydroxymethyl-13-trans-17-trans-pro-                                        stadiene                                      468  319   292        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-prostene                          469  319   292        108       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-19,20-dinor-13-trans-prostene              470  319   292        109       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-18,19,20-trinor-13-trans-prostene          471  319   292        110       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-20-nor-13-trans-prostene                   472  319   292        144       1,9-dioxo-11α,16-dihydroxy-17-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene               473  319   292        112       1,9-dioxo-11α,16-dihydroxy-20-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene               474  319   292        113       1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                    1-hy-                                                                         droxymethyl-13-trans-prostene                 475  319   292        139a      1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -20-                                                                          ethyl-1-hydroxymethyl-13-trans-prostene       476  319   292        115       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-17-cis-prostadiene                477  319   292        135       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene               478  319   292        136       1,9-dioxo-11α,16-dihydroxy-17,17,20-                                    tri-                                                                          methyl-1-hydroxymethyl-13-trans-prostene      479  319   292        137       1,9-dioxo-11α,16-dihydroxy-16,20-dim                                    eth-                                                                          yl-1-hydroxymethyl-13-trans-prostene          480  319   292        138       1,9-dioxo-11α,16-dihydroxy-17,17-dim                                    eth-                                                                          yl-1-hydroxymethyl-13-trans-prostene          481  319   292        139       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-17-trans-prosta-                                       diene                                         482  319   292        149       1,9-dioxo-11α,16-dihydroxy-20-methyl                                    -1-                                                                           hydroxymethyl-13-trans-17-trans-prosta-                                       diene                                         483  319   292        150       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene               485  319   292        151       1,9-dioxo-11α,16-dihydroxy-17,20-dim                                    eth-                                                                          yl-1-hydroxymethyl-13-trans-prostene          486  319   292        152       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-17-trans-prostadiene              487  319   292        153       1,9-dioxo-11α,16(R)-dihydroxy-1-hydr                                    oxy-                                                                          methyl-13-trans-prostene                      488  319   292        154       1,9-dioxo-11α,16(S)-dihydroxy-1-hydr                                    oxy-                                                                          methyl-13-trans-prostene                      489  319   292        148a      1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                    1-hy-                                                                         droxymethyl-13-trans-17-trans-prostadiene     490  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-1-                                    hydroxy-                                                            phenylmethoxy-                                                                          methyl-13-trans-prostadiene                                         1-trans-octene                                                                (U.S. Pat. No.                                                                3,873,607).                                             491  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-20                                    -methyl-1-                                                          phenylmethoxy-1-                                                                        hydroxymethyl-13-trans-prostene                                     trans-nonene                                                                  (U.S. Pat. No.                                                                3,873,607).                                             492  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-20                                    -ethyl-1-                                                           phenylmethoxy-                                                                          hydroxymethyl-13-trans-prostene                                     1-trans-decene                                                                (U.S. Pat. No.                                                                3,873,607).                                             493  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-dimeth-                                                         phenylmethoxy-                                                                          yl-1-hydroxymethyl-13-trans-prostene                                4,4-dimethyl-1-                                                               trans-octene                                                                  (U.S. Pat. No.                                                                3,873,607).                                             494  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihyroxy-17,                                    17-dimeth-                                                          phenylmethoxy-                                                                          yl-1-hydroxymethyl-13-trans-prostene                                5,5-dimethyl-1-                                                               trans-octene                                                                  (U.S. Pat. No.                                                                3,873,607).                                             495  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-16                                    -methyl-1-                                                          phenylmethoxy-                                                                          hydroxymethyl-13-trans-prostene                                     4-methyl-1-                                                                   trans-octene                                                                  (U.S. Pat. No.                                                                3,876,690).                                             496  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-16                                    -ethyl-1-                                                           phenylmethoxy-                                                                          hydroxymethyl-13-trans-prostene                                     4-ethyl-1-                                                                    trans-octene                                                                  (U.S. Pat. No.                                                                3,876,690).                                             497  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-17                                    ,20-tetra-                                                          phenylmethoxy-                                                                          nor-16-cyclopentyl-1-hydroxymethyl-13-                              4-cyclopentyl-                                                                          trans-prostene                                                      1-trans-butene-                                                               (U.S. Pat. No.                                                                3,884,969).                                             498  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-16                                    ,20-penta-                                                          phenylmethoxy-                                                                          nor-15-cyclohexyl-1-hydroxymethyl-13-                               3-cyclohexyl-                                                                           trans-prostene                                                      1-trans-pentene                                                               (U.S. Pat. No.                                                                3,884,969).                                             499  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-18                                    ,20-trinor-                                                         phenylmethoxy-                                                                          17-cyclohexyl-1-hydroxymethyl-13-trans-                             5-cyclohexyl-                                                                           prostene                                                            1-trans-pentene                                                               (U.S. Pat. No.                                                                3,884,969).                                             500  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-19                                    ,20-dinor-                                                          phenylmethoxy-                                                                          18-cyclopentyl-1-hydroxymethyl-13-trans-                            6-cyclopentyl-                                                                          prostene                                                            1-trans-hexene                                                                (U.S. Pat. No.                                                                3,884,969).                                             501  319   292        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-1-                                                          methylsilyloxy-                                                                         hydroxymethyl-13-trans-prostene                                     trans-1-octene                                                                (Example 125)                                           502  319   292        1-iodo-3-methyl-                                                                        1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-20-                                                         3-trimethylsilyl-                                                                       ethyl-1-hydroxymethyl-13-trans-prostene                             oxy-trans-1-decene                                                            (Example 190a)                                          503  320   292        159       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-fluorophenoxy-1-hydroxy-                                        methyl-13-trans-prostene                      504  320   292        186       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-phenoxy-1-hydroxymethyl-13-                                       trans-prostene                                505  320   292        181       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-bromophenoxy-1-hydroxy-                                         methyl-13-trans-prostene                      506  320   292        182       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-t-butylphenoxy-1-hydroxy-                                       methyl-13-trans-prostene                      507  320   292        183       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-methoxyphenoxy-1-hydroxy-                                       methyl-13-trans-prostene                      508  320   292        184       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-m-chlorophenoxy-1-hydroxy-                                        methyl-13-trans-prostene                      509  320   292        180       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-m-trifluorophenoxy-1-hydroxy-                                     methyl-13-trans-prostene                      510  320   292        185       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-(3,4-dichlorophenoxy)-1-hy-                                       droxymethyl-13-trans-prostene                 511  320   292        186b      1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-phenyl-1-hydroxymethyl-13-trans-                                       prostene                                      512  320   292        186e      1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-(m-trifluoromethylphenyl)-1-hy-                                        droxy-13-trans-prostene                       513  320   292        186d      1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                     13-trans-prostene                             514  319   293        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-1-                                    hydroxy-                                                            phenylmethoxy-                                                                          methyl-trans-prostadiene                                            1-trans-octene                                                                (U.S. Pat. No.                                                                3,873,607).                                             515  319   293        190       1,9-dioxo-11α ,15α-dihydroxy-1                                    5-methyl-1-                                                                   hydroxymethyl-2-nor-13-trans-prostene         516  319   293        1-iodo-3-tri-                                                                           1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-di-                                                             phenylmethoxy-                                                                          methyl-1-hydroxymethyl-2-nor-13-trans-                              5,5-dimethyl-                                                                           prostene                                                            octene (U.S.                                                                  Pat. No. 3,873,607)                                     517  319   293         13       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-tri-                                                                      methylene-1-hydroxymethyl-2-nor-13-trans-                                     prostene                                      518  319   293         76       erythro-1,9-dioxo-11α,15α,16-t                                    rihydroxy-                                                                    1-hydroxymethyl-2-nor-13-trans-prostene       519  319   293         69       threo-1,9-dioxo-11α,15α-trihyd                                    roxy-1-                                                                       hydroxymethyl-2-nor-13-trans-prostene         520  319   293         74       erythro-1,9-dioxo-11α,15α-dihy                                    droxy-16-                                                                     methoxy-1-hydroxymethyl-2-nor-13-trans-                                       prostene                                      521  319   293        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-2-nor-13-trans-prostene                    522  319   293        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-2-nor-13-trans-prostene         523  319   293        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-2-nor-13-trans-prostene         524  320   293        186       1,9-dioxo-11α,15α-dihydroxy-2,                                    17,18,19,-                                                                    20-pentanor-16-phenoxy-1-hydroxymethyl-                                       13-trans-prostene                             525  320   293        180       1,9-dioxo-11α,15α-dihydroxy-2,                                    17,18,19,-                                                                    20-pentanor-16-m-trifluoromethylphenoxy-                                      1-hydroxymethyl-13-trans-prostene             526  319   293        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    1-                                                                            hydroxymethyl-2-nor-13-trans-prostene         527  320   293        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    rop-                                                                          yl-1-hydroxymethyl-2-nor-13-trans-prost-                                      ene                                           528  320   293        186b      1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-phenyl-1-hydroxymethyl-13-                                        trans-prostene                                529  319   293        186e      1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-(m-trifluorophenyl)-1-hy-                                         droxymethyl-13-trans-prostene                 530  319   293        186d      1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-(p-methoxyphenyl)-1-hy-                                           droxymethyl-13-trans-prostene                 __________________________________________________________________________

EXAMPLES 531-553

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 35 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table35. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymmetric carbon atoms on the β-chain (the chaincontaining C₁₃. . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 35                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-1-hydroxymethylprostene and           Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    531  319   292        246     nat(and ent)-1,9-dioxo-11α,15-dihydrox                                  y-                                                                            15,16-tetramethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-prostene           532  320   292        245     nat(and ent)-1,9-dioxo-11α,16-dihydrox                                  y-                                                                            16,17-tetramethylene-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-prostene                 533  319   292        243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-                                       11α,15-dihydroxy-15,16-trimethylene-1-                                  2                                                                             hydroxymethyl-13-trans-prostene                 534  319   292        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  M                                                                             hydroxymethyl-13-trans-prostene                 535  319   292        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  a                                                                             hydroxymethyl-13-trans-prostene                 536  319   292        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-trimethylene-17,18,19,20-tetranor-                                      1-hydroxymethyl-13-trans-prostene               537  320   292        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-pentamethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-prostene           538  319   292        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-,15,17-dimethylene-1-                                  3                                                                             hydroxymethyl-13-trans-prostene                 539  319   292        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-dimethylene-1-h                                  y-                                                                            droxymethyl-13-trans-prostene                   540  319   292        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-tetramethylene-                                  p                                                                             hydroxymethyl-13-trans-prostene                 541  319   292        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihdroxy-15,16-tetramethylene-1                                  -                                                                             hydroxymethyl-13-trans-prostene                 542  320   292        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-prost                                       ene                                             543  320   292        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-prost-                                      ene                                             544  319   292        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene               545  319   292        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene               546  320   292        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α-15,dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene               547  320   292        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene               548  319   292        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-prost-                                      ene                                             549  319   292        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy15,17-trimethylene-19,                                  -                                                                             20-dinor-1-hydroxymethyl-13-trans-prost-                                      ene                                             550  320   292        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-prostene        551  320   292        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-prostene        552  320   292        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-prostene           553  320   292        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α16-dihydroxy-16,17-trimethylene-16-                                  n                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-prostene           __________________________________________________________________________

EXAMPLES 554-637

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 36 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers are listed in Table 36; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomer is also formedand is part of this invention.

In those cases where the initial conjugate addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 36                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example    1,9-dioxo-1-hydroxymethylprostene            __________________________________________________________________________    554  319   287         49        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     0                                                                             16-trimethylene-20-nor-5-cis-13-trans-                                        prostadiene                                  555  319   287         50        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     6                                                                             16-trimethylene-20-methyl-5-cis-13-trans-                                     J                                                                             prostadiene                                  556  319   287         51        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     u                                                                             16-trimethylene-20-ethyl-5-cis-13-trans-                                      l                                                                             prostadiene                                  557  320   287        193        1,9-dioxo-16-hydroxy-16-cyclopropyl-20-                                       ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  558  320   287        195        1,9-dioxo-16-vinyl-20-ethyl-1-                                                hydroxymethyl-5-cis-13-trans-prostadiene                                      N                                            559  320   287        192        1,9-dioxo-11α,16-dihydroxy-16-cyclo                                     propyl-                                                                       1-hydroxymethyl-5-cis-13-trans-prostadi-                                      0                                                                             ene                                          560  319   287         13        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     7                                                                             16-trimethylene-13-trans-5-cis-prostadien                                     e                                            561  320   287         210a      1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-                                      u                                                                             vinyl-5-cis-13-trans-prostadiene             562  319   287         74        dl-erythro-1,9-dioxo-15-hydroxy-16-meth-                                      g                                                                             oxy-1-hydroxymethyl-5-cis-13-prosta-                                          diene                                        563  319   287         77        dl-erythro-1,9-dioxo-15-hydroxy-16-ethoxy                                     -                                                                             1-hydroxymethyl-5-cis-13-trans-prostadi-                                      8                                                                             ene                                          564  319   287         83        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-nor-5-cis-13-trans-                                          prostadiene                                  565  319   287         84        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-methyl-5-cis-13-trans-                                       prostadiene                                  566  319   287         85        dl-erythro-1,9-dioxo-15,16-dihydroxy-20-                                      S                                                                             ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  567  319   287         86        dl-erythro-1,9-dioxo-15,16-dihydroxy-19-                                      e                                                                             methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  568  319   287         87        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-5-cis-13-trans-17-trans-                                        prostatriene                                 569  319   287         69        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      p                                                                             droxymethyl-5-cis-13-trans-17-trans-prost                                     adiene                                       570  319   287         88        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        nor-1-hydroxymethyl-5-cis-13-trans-                                           prostadiene                                  571  319   287         76        dl-erythro-1,9-dioxo-11α,15,16-trih                                     y-                                                                            droxy-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  572  319   287         89        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  573  319   287         90        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene                                  574  319   287         91        dl-threo-1,9-dioxo-15,16-dihydroxy-19-                                        methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  575  319   287         92        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      O                                                                             droxymethyl-5-cis-13-trans-17-trans-                                          prostatriene                                 576  319   287        107        1,9-dioxo-16-hydroxy-1-hydroxymethyl-5-                                       cis-13-trans-prostadiene                     577  319   287        108        1,9-dioxo-16-hydroxy-1-hydroxymethyl-19,-                                     c                                                                             20-dinor-5-cis-13-trans-prostadiene          578  319   287        109        1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                     t                                                                             19,20-trinor-5-cis-13-trans-prostadiene      579  319   287        110        1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                      1                                                                             nor-5-cis-13-trans-prostadiene               580  319   287        144        1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy-                                     0                                                                             methyl-5-cis-13-trans-prostadiene            581  319   287        112        1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     N                                                                             methyl-5-cis-13-trans-prostadiene            582  319   287        113        1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      o                                                                             methyl-5-cis-13-trans-prostadiene            583  319   287         139a      1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                      v                                                                             1-hydroxymethyl-5-cis-13-trans-prostadi-                                      1                                                                             ene                                          584  319   287        115        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      1                                                                             trans-17-cis-5-cis-prostatriene              585  319   287        135        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     D                                                                             methyl-5-cis-13-trans-prostadiene            586  319   287        136        1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                      e                                                                             1-hydroxymethyl-5-cis-13-trans-prostadi-                                      c                                                                             ene                                          587  319   287        137        1,9-dioxo-16-hydroxy-16,20-dimethyl-1-hy-                                     1                                                                             droxymethyl-13-trans-5-cis-prostadiene       588  319   287        138        1,9-dioxo-16-hydroxy-17,17-dimethyl-1-hy-                                     2                                                                             droxymethyl-5-cis-13-trans-prostadiene       589  319   287        139        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     methyl-13-trans-17-trans-5-cis-prostri-                                       ene                                          590  319   287        149        1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     N                                                                             methyl-13-trans-17-trans-5-cis-prostri-                                       ene                                          591  319   287        150        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     O                                                                             methyl-5-cis-13-trans-prostadiene            592  319   287        151        1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                     droxymethyl-5-cis-13-trans-prostadiene       593  319   287        152        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      trans-17-trans-5-cis-13-trans-prostadiene    594  319   287        153        1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl-                                      5-cis-13-trans-prostadiene                   595  319   287        154        1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                      5-cis-13-trans-prostadiene                   596  319   287         148a      1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      methyl-5-cis-13-trans-17-trans-prostatri-                                     1                                                                             ene                                          597  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymeth                                     yl-5-                                                              ylmethoxy-1-trans-                                                                       cis-13-trans-prostadiene                                           octene (U.S. Pat.                                                             No. 3,873,607).                                         598  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-methyl-1-h                                     ydr-                                                               ylmethoxy-1-trans-                                                                       oxymethyl-5-cis-13-trans-prostadiene                               nonene (U.S. Pat.                                                             No. 3,873,607).                                         599  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-ethyl-1-hy                                     droxy-                                                             ylmethoxy-1-trans-                                                                       methyl-5-cis-13-trans-prostadiene                                  decene (U.S. Pat.                                                             No. 3,873,607).                                         600  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethy                                     l-1-                                                               ylmethoxy-4,4-di-                                                                        hydroxymethyl-5-cis-13-trans-prostadiene                                      Z                                                                  methyl-1-trans-                                                               octene (U.S. Pat.                                                             No. 3,873,607).                                         601  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,17-dimethy                                     l-1-                                                               ylmethoxy-5,5-di-                                                                        hydroxymethyl-5-cis-13-trans-prostadiene                                      '                                                                  methyl-1-trans-                                                               octene (U.S. Pat.                                                             No. 3,873,607).                                         602  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-methyl-1-h                                     ydr-                                                               ylmethoxy-4-meth-                                                                        oxymethyl-5-cis-13-trans-prostadiene                               yl-1-trans-octene                                                             (U.S. Pat. No.                                                                3,873,690).                                             603  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-ethyl-1-hy                                     droxy-                                                             ylmethoxy-4-ethyl-                                                                       methyl-5-cis-13-trans-prostadiene                                  1-trans-octene                                                                (U.S. Pat. No.                                                                3,876,690).                                             604  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,20-tetrano                                     r-1-                                                               ylmethoxy-4-cyclo-                                                                       cyclopentyl-1-hydroxymethyl-5-cis-13-                              pentyl-1-trans-                                                                          trans-prostadiene                                                  butene (U.S. Pat.                                                             No. 3,884,969).                                         605  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,20-pentano                                     r-15-                                                              ylmethoxy-3-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-5-cis-13-                               hexyl-1-trans-                                                                           trans-prostadiene                                                  pentene (U.S. Pat.                                                            No. 3,884,969).                                         606  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-18,20-trinor-                                     17-                                                                ylmethoxy-5-cyclo-                                                                       cyclophexyl-1-hydroxymethyl-5-cis-13-                              hexyl-1-trans-                                                                           trans-prostadiene                                                  pentene (U.S. Pat.                                                            No. 3,884,969).                                         607  319   287        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-19,20-dinor-1                                     8-                                                                 ylmethoxy-6-cyclo-                                                                       cyclopentyl-1-hydroxymethyl-5-cis-13-                              pentyl-1-trans-                                                                          trans-prostadiene                                                  hexene (U.S. Pat.                                                             No. 3,884,969).                                         608  319   287        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-1-h                                     ydr-                                                               trimethylsilyl-                                                                          oxymethyl-5-cis-13-trans-prostadiene                               oxy-trans-1-octene                                                            (Example 125)                                           609  319   287        1-iodo-3-methyl-                                                                         1,9-dioxo-15α-hydroxy-15-methyl-20-                                     ethyl-                                                             3-trimethylsil-                                                                          1-hydroxymethyl-5-cis-13-trans-prostadi-                                      s                                                                  yloxy-trans-1-dec-                                                                       ene                                                                ene (Example 190a)                                      610  320   287        159        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-fluorophenoxy-1-hydroxymethyl-5-                                     Z                                                                             cis-13-trans-prostadiene                     611  320   287        186        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-phenoxy-1-hydroxymethyl-5-cis-13-                                      .                                                                             trans-prostadiene                            612  320   287        181        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-bromophenoxy-1-hydroxymethyl-5-                                      d                                                                             cis-13-trans-prostadiene                     613  320   287        182        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-t-butylphenoxy-1-hydroxymethyl-                                      N                                                                             5-cis-13-trans-prostadiene                   614  320   287        183        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                      n                                                                             5-cis-13-trans-prostadiene                   615  320   287        184        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-chlorophenoxy-1-hydroxymethyl-5-                                     .                                                                             5-cis-13-trans-prostadiene                   616  320   287        180        1,9-dioxo-11α,15α-dihydroxy-1                                     7,18,19,20-                                                                   tetranor-m-trifluorophenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene            617  320   287        185        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene            618  320   287         186b      1,9-dioxo-15α-hydroxy-18,19,20-trin                                     or-17-                                                                        phenyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene                                  619  320   287         186e      1,9-dioxo-15α-hyydroxy-18,19,20-tri                                     nor-17-                                                                       (m-trifluoromethylphenyl)-1-hydroxymeth-                                      o                                                                             yl-5-cis-13-trans-prostadiene                620  320   287         186d      1,9-dioxo-15α-hydroxy-18,19,20-trin                                     or-17-                                                                        (p-methoxyphenyl)-1-hydroxymethyl-5-cis-                                      i                                                                             13-trans-prostadiene                         621  319   288        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-dihydroxy-1-hydroxyme                                     thyl-                                                              ylmethoxy-1-trans-                                                                       2-nor-5-cis-13-trans-prostadiene                                   octene (U.S. Pat.                                                             No. 3,873,607).                                         622  319   288        190        1,9-dioxo-15α-hydroxy-15-methyl-1-h                                     ydr-                                                                          oxymethyl-2-nor-5-cis-13-trans-prostadi-                                      n                                                                             ene                                          623  319   288        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethy                                     l-1-                                                               ylmethoxy-5,5-di-                                                                        hydroxymethyl-2-nor-5-cis-13-trans-                                methyl octene                                                                            prostadiene                                                        (U.S. Pat. No.                                                                3,873,607).                                             624  319   288         13        1,9-dioxo-15α-hydroxy-16,16-trimeth                                     ylene-                                                                        1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene                                  625  319   288         76        erythro-1,9-dioxo-15α,16-dihydroxy-                                     1-hy-                                                                         droxymethyl-2-nor-5-cis-13-trans-prosta-                                      7                                                                             diene                                        626  319   288         69        threo-1,9-dioxo-15α,16-dihydroxy-1-                                     hydro-                                                                        xymethyl-2-nor-5-cis-13-trans-prostadiene                                     d                                            627  319   288         74        erythro-1,9-dioxo-15α-hydoxy-16-met                                     h-                                                                            oxy-1-hydroxymethyl-2-nor-5-cis-13-trans-                                     f                                                                             prostadiene                                  628  319   288        107        1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                       nor-5-cis-13-trans-prostadiene               629  319   288        130        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     f                                                                             methyl-2-nor-5-cis-13-trans-prostadiene      630  319   288        134        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     e                                                                             methyl-2-nor-5-cis-13-trans-17-trans-                                         prostatriene                                 631  320   288        186        1,9-dioxo-15α-hydroxy-2,17,18,19,20                                     -pent-                                                                        anor-16-phenoxy-1-hydroxymethyl-5-cis-13-                                     e                                                                             trans-prostadiene                            632  320   288        180        1,9-dioxo-15α-hydroxy-2,17,18,19,20                                     -pent-                                                                        anor-16-m-trifluoromethylphenoxy-1-hydro-                                     t                                                                             xymethyl-5-cis-13-trans-prostadiene          633  319   288        194        1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                      i                                                                             methyl-2-nor-5-cis-13-trans-prostadiene      634  320   288        198        1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                     a                                                                             droxymethyl-2-nor-5-cis-13-trans-prosta-                                      l                                                                             diene                                        635  320   288         186b      1,9-dioxo-15α-hydroxy-2,18,19,20-te                                     tra-                                                                          nor-17-phenyl-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene                            636  319   288         186e      1,9-dioxo-15α-hydroxy-2,18,19,20-te                                     tra-                                                                          nor-17-(m-trifluorophenyl)-1-hydroxymeth-                                     8                                                                             yl-5-cis-13-trans-prostadiene                 637a                                                                              319   288         186d      1,9-dioxo-15α-hydroxy-2,18,19,20-te                                     tra-                                                                          nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                     Z                                                                             5-cis-13-trans-prostadiene                    637b                                                                              320   288         210c      1,9-dioxo-16-hydroxy-16-ethyl-1-hydroxy-                                      9                                                                             methyl-2-nor-5-cis-13-trans-prostadiene      __________________________________________________________________________

EXAMPLES 638-660

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 37 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table37. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymetric carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 37                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-1-hydroxymethylprostene and           Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    638  319   287        246     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     tetramethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-5-cis-13-trans-prostadiene        639  320   287        245     nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                     tetramethylene-18,19,20-trinor-1-hydr-                                        oxymethyl-5-cis-13-trans-prostadiene            640  319   287        243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-                                       15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-5-cis-13-trans-prostadiene               641  319   287        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-13-trans-5-cis-prostadiene               642  319   287        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-13-trans-5-cis-prostadiene               643  319   287        247     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     trimethylene-17,18,19,20-tetranor-1-hy-                                       droxymethyl-13-trans-5-cis-prostadiene          644  320   287        248     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     pentamethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-5-cis-prostadiene        645  319   287        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxoene-                                   N                                                                             15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene               646  319   287        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene               647  319   287        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-tetramethylene-1-hy-                                         droxymethyl-13-trans-5-cis-prostadiene          648  319   287        253     nat-15S,16S-(and ent-15R,16R)-1,9,-dioxo-                                     15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene            649  320   287        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-5-cis-                                           prostadiene                                     650  320   287        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-5-cis-                                           prostadiene                                     651  319   287        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(4-flu-                                      orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      oxymethyl-13-trans-5-cis-prostadiene            652  319   287        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(4-flu-                                      orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      oxymethyl-13-trans-5-cis-prostadiene            653  320   287        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-5-cis-prostadiene        654  320   287        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-5-cis-prostadiene        655  319   287        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-5-cis-prosta-                                    diene                                           656  319   287        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene                                          657  320   287        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-20-methyl-                                      1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             658  320   287        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-20-methyl-                                      1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene                                             659  320   287        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-5-cis-prostadiene        660  320   287        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-5-cis-prostadiene        __________________________________________________________________________

EXAMPLES 662-746

By the methods of described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 38 areprepared by the indicated method from the indicated vinyl idoide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers are listed in Table 38; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomers are alsoformed and are part of this invention.

In those cases where the initial conjugate-addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 38                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example   1,9-dioxo-1-hydroxymethylprostene             __________________________________________________________________________    662  319   284        49        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     N                                                                             16-trimethylene-20-nor-13-trans-prostene      663  319   284        50        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     O                                                                             16-trimethylene-20-methyl-13-trans-prost-                                     ]                                                                             ene                                           664  319   284        51        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     Z                                                                             16-trimethylene-20-ethyl-13-trans-prost-                                      ene                                           665  320   284        193       1,9-dioxo-16-hydroxy-16-cyclopropyl-20-                                       ethyl-1-hydroxymethyl-13-trans-prostene       666  320   284        195       1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1-                                     1                                                                             hydroxymethyl-13-trans-prostene               667  320   284        192       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-                                        hydroxymethyl-13-trans-prostene               668  319   284        13        1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     0                                                                             16-trimethylene-13-trans-prostene             669  320   284        210a      1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-                                      vinyl-13-trans-prostene                       670  319   284        74        dl-erythro-1,9-dioxo-15-dihydroxy-16-meth-                                    Z                                                                             oxy-1-hydroxymethyl-13-trans-prostene         671  319   284        77        dl-erythro-1,9-dioxo-16-dihydroxy-16-eth-                                     1                                                                             oxy-1-hydroxymethyl-13-trans-prostene         672  319   284        83        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-nor-13-trans-prostene        673  319   284        84        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-methyl-13-trans-prost-                                       ene                                           674  319   284        85        dl-erythro-1,9-dioxo-15,16-dihydroxy-20-                                      ethyl-1-hydroxymethyl-13-trans-prostene       675  319   284        86        dl-erythro-1,9-dioxo-15,16-dihydroxy-19-                                      methyl-1-hydroxymethyl-13-trans-prostene      676  319   284        87        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-13-trans-17-trans-prosta-                                       diene                                         677  319   284        69        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      droxymethyl-13-trans-prostene                 678  319   284        88        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        nor-1-hydroxymethyl-13-trans-prostene         679  319   284        76        dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-13-trans-prostene               680  319   284        89        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        methyl-1-hydroxymethyl-13-trans-prostene      681  319   284        90        dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        ethyl-1-hydroxymethyl-13-trans-prostene       682  319   284        91        dl-threo-1,9-dioxo-15,16-dihydroxy-19-                                        methyl-1-hydroxymethyl-13-trans-prostene      683  319   284        92        dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      droxymethyl-13-trans-17-trans-prostadiene                                     N                                             684  319   284        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      trans-prostene                                685  319   284        108       1,9-dioxo-16-hydroxy-1-hydroxymethyl-19,-                                     O                                                                             20-dinor-13-trans-prostene                    687  319   284        109       1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                     1                                                                             19,20-trinor-13-trans-prostene                688  319   284        110       1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                      nor-13-trans-prostene                         689  319   284        144       1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy-                                     Z                                                                             methyl-13-trans-prostene                      690  319   284        112       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     1                                                                             methyl-13-trans-prostene                      691  319   284        113       1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      methyl-13-trans-prostene                      692  319   284        139a      1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                      1-hydroxymethyl-13-trans-prostene             693  319   284        115       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      trans-17-cis-prostadiene                      694  319   284        135       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     2                                                                             methyl-13-trans-prostene                      695  319   284        136       1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                      1-hydroxymethyl-13-trans-prostene             696  319   284        137       1,9-dioxo-16-hydroxy-16,20-dimethyl-1-                                        hydroxymethyl-13-trans-prostene               697  319   284        138       1,9-dioxo-16-hydroxy-17,17-dimethyl-1-                                        hydroxymethyl-13-trans-prostene               698  319   284        139       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     Z                                                                             methyl-13-trans-17-trans-prostadiene          699  319   284        149       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     1                                                                             methyl-13-trans-17-trans-prostadiene          700  319   284        150       1,9-dioxo-16-hydroxy-16-methyl-1-hydr-                                        oxymethyl-13-trans-prostene                   701  319   284        151       1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                     3                                                                             droxymethyl-13-trans-prostene                 702  319   284        152       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      trans-17-trans-prostadiene                    703  319   284        153       1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl-                                      13-trans-prostene                             704  319   284        154       1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                      13-trans-prostene                             705  319   284        148a      1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      methyl-13-trans-17-trans-prostadiene          706  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-l-hydroxymethy                                    l-13- -   ylmethoxy-1-trans- trans-prostad                                    iene                                                                octene (U.S. Pat.                                                             No. 3,873,607).                                         707  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-20-methyl-1-hy                                    droxy-                                                              ylmethoxy-1-trans-                                                                      methyl-13-trans-prostene                                            nonene (U.S. Pat.                                                             No. 3,873,607).                                         708  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-20-ethyl-1-hyd                                    roxy-                                                               ylmethoxy-1-trans-                                                                      methyl-13-trans-prostene                                            decene (U.S. Pat.                                                             No. 3,873,607).                                         709  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16,16-dimethyl                                    -1-                                                                 ylmethoxy-4,4-di-                                                                       hydroxymethyl-13-trans-prostene                                     methyl-1-trans-oct-                                                           ene (U.S. Pat. No.                                                            3,873,607).                                             710  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-17,17-dimethyl                                    -1-                                                                 ylmethoxy-5,5-di-                                                                       hydroxymethyl-13-trans-prostene                                     methyl-1-trans-oct-                                                           ene (U.S. Pat. No.                                                            3,873,607).                                             711  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16-methyl-1-hy                                    droxy-                                                              ylmethoxy-4-meth-                                                                       methyl-13-trans-prostene                                            yl-1-trans-octene                                                             (U.S. Pat. No.                                                                3,876,690).                                             712  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16-ethyl-1-hyd                                    r-                                                                  ylmethoxy-4-ethyl-                                                                      oxymethyl-13-trans-prostene                                         1-trans-octene                                                                (U.S. Pat. No.                                                                3,876,690).                                             713  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-17,20-tetranor                                    -16-                                                                ylmethoxy-4-cyclo-                                                                      cyclopentyl-1-hydroxymethyl-13-trans-                               pentyl-1-trans-                                                                         prostene                                                            butene (U.S. Pat.                                                             No. 3,884,969).                                         714  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16,20-pentanor                                    -15-                                                                ylmethoxy-3-cyclo-                                                                      cyclohexyl-1-hydroxymethyl-13-trans-                                hexyl-1-trans-pen-                                                                      prostene                                                            tene (U.S. Pat. No.                                                           3,884,969).                                             715  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-18,20-trinor-1                                    7-                                                                  ylmethoxy-5-cyclo-                                                                      cyclohexyl-1-hydroxymethyl-13-trans-                                hexyl-1-trans-                                                                          prostene                                                            pentene (U.S. Pat.                                                            No. 3,884,969).                                         716  319   284        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-19,20-dinor-18                                    -                                                                   ylmethoxy-6-cyclo-                                                                      cyclopentyl-1-hydroxymethyl-13-trans-                               pentyl-1-trans-                                                                         prostene                                                            hexene (U.S. Pat.                                                             No. 3,884,969).                                         717  319   284        1-iodo-3-methyl-                                                                        1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                    dr-                                                                 3-trimethylsilyl-                                                                       oxymethyl-13-trans-prostene                                         oxy-trans-1-octene                                                            (Example 125).                                          718  319   284        1-iodo-3-methyl-                                                                        1,9-dioxo-15α-hydroxy-15-methyl-20-e                                    thyl-                                                               3-trimethylsilyl-                                                                       1-hydroxymethyl-13-trans-prostene                                   oxy-trans-1-decene                                                            (Example 190a).                                         719  320   284        159       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-fluorophenoxy-1-hydroxymethyl-                                       13-trans-prostene                             720  320   284        186       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-phenoxy-1-hydroxymethyl-13-trans-                                      prostene                                      721  320   284        181       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-bromophenoxy-1-hydroxymethyl-                                        trans-prostene                                722  320   284        182       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-t-butylphenoxy-1-hydroxymethyl-                                      13-trans-prostene                             723  320   284        183       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                      13-trans-prostene                             724  320   284        184       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-m-chlorophenoxy-1-hydroxymethyl-                                       13-trans-prostene                             725  320   284        180       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-m-trifluorophenoxy-1-hydroxymethyl-                                    .                                                                             13-trans-prostene                             726  320   284        185       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                       methyl-13-trans-prostene                      727  320   284        186b      1,9-dioxo-15α-hydroxy-18,19,20-trino                                    r-17-                                                                         phenyl-1-hydroxymethyl-13-trans-prostene      728  320   284        186e      1,9-dioxo-15α-hydroxy-18,19,20-trino                                    r-17-                                                                         (m-trifluoromethylphenyl)-1-hydroxymeth-                                      yl-13-trans-prostene                          729  320   284        186d      1,9-dioxo-15α-hydroxy-18,19,20-trino                                    r-17-                                                                         (p-methoxyphenyl)-1-hydroxymethyl-13-                                         trans-prostene                                730  319   285        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-1-hydroxymethy                                    l-2-                                                                ylmethoxy-1-trans-                                                                      nor-13-trans-prostadiene                                            octene (U.S. Pat.                                                             No. 3,873,607).                                         731  319   285        190       1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                    droxy-                                                                        methyl-2-nor-13-trans-prostene                732  319   285        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16,16-dimethyl                                    -1-hy-                                                              ylmethoxy-5,5-di-                                                                       droxymethyl-2-nor-13-trans-prostene                                 methyl-octene (U.S.                                                           Pat. No. 3,873,607).                                    733  319   285        13        1,9-dioxo-15α-hydroxy-16,16-trimethy                                    lene-                                                                         1-hydroxymethyl-2-nor-13-trans-prostene       734  319   285        76        erythro-1,9-dioxo-15α,-16-dihydroxy-                                    1-hy-                                                                         droxymethyl-2-nor-13-trans-prostene           735  319   285        69        threo-1,9-dioxo-15α,16-dihydroxy-1-h                                    ydr-                                                                          oxymethyl-2-nor-13-trans-prostene             736  319   285        74        erythro-1,9-dioxo-15α-hydroxy-16-met                                    hoxy-                                                                         1-hydroxymethyl-2-nor-13-trans-prostene       737  319   285        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                       nor-13-trans-prostene                         738  319   285        130       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     N                                                                             methyl-2-nor-13-trans-prostene                739  319   285        134       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     O                                                                             methyl-2-nor-13-trans-17-trans-prostadiene                                    8                                             740  320   285        186       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                    penta-                                                                        nor-16-phenoxy-1-hydroxymethyl-13-trans-                                      prostene                                      741  320   285        180       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                    penta-                                                                        nor-16-m-trifluoromethylphenoxy-1-hydroxy-                                    b                                                                             methyl-13-trans-prostene                      742  319   285        194       1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                      methyl-2-nor-13-trans-prostene                743  320   285        198       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                     o                                                                             droxymethyl-2-nor-13-trans-prostene           744  320   285        186b      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                    ranor-                                                                        17-phenyl-1-hydroxymethyl-13-trans-prost-                                     t                                                                             ene                                           745  319   285        186e      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                    ranor-                                                                        17-(m-trifluorophenyl)-1-hydroxymethyl-                                       13-trans-prostene                             746  319   285        186d      1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                    ranor-                                                                        17-(p-methoxyphenyl)-1-hydroxymethyl-13-                                      trans-prostene                                __________________________________________________________________________

EXAMPLES 747-769

By the methods described hereinabove in Examples 319 and 320, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 39 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereosiomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table39. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymetric carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 39                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-1-hydroxymethylprostene and           Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    747  319   284        246     nat-(and ent)-1,9-dioxo-15-hydroxy-15,-                                       16-tetramethylene-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene               748  320   284        245     nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                     tetramethylene-18,19,20-trinor-1-hydroxy-                                     methyl-13-trans-prostene                        749  319   284        243     nat-15S,16R(and ent-15R,16S)-1,9-dioxo-15-                                    hydroxy-15,16-trimethylene-1-hydroxymeth-                                     yl-13-trans-prostene                            750  319   284        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-13-trans-prostene                        751  319   284        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-13-trans-prostene                        752  319   284        247     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     trimethylene-17,18,19,20-tetranor-1-hy-                                       droxymethyl-13-trans-prostene                   753  320   284        248     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     pentamethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene                 754  319   284        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-prostene                        755  319   284        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-prostene                        756  319   284        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-prostene                     757  319   284        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-prostene                     758  320   284        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-prostene           759  320   284        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-prostene           760  319   284        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(4-                                          fluorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene                 761  319   284        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(4-flu-                                      orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      oxymethyl-13-trans-prostene                     762  320   284        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene                 763  320   284        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene                 764  319   284        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-prostene           765  319   284        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-prostene           766  320   284        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-20-meth-                                        yl-1-hydroxymethyl-13-trans-prostene            767  320   284        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-20-meth-                                        yl-1-hydroxymethyl-13-trans-prostene            768  320   284        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-prostene                 769  320   284        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-prostene                 __________________________________________________________________________

EXAMPLE 770 Preparation of l-9-oxo-15(S)-acetoxy prostanoyl chloride

To a solution of 0.5 g of l-9-oxo-15(S)-acetoxy prostanoic acid in 10 mlof benzene at 0° C. with stirring is added 0.5 ml of oxalyl chloride.The mixture is stirred at room temperature for 21/2 hours. The solventand excess oxalyl chloride is removed at reduced pressure. The residueis dissolved in hexane and filtered. The solvent is removed giving thetitle compound.

EXAMPLE 771 Preparation ofl-1,9-dioxo-15(S)-acetoxy-1-hydroxymethyl-prostene

To a solution of 11.9 mmol of diazomethane in ether at 0° C. withstirring is added dropwise a solution of 2.99 mmol ofl-9-oxo-15(S)-acetoxy prostanoyl chloride (Example 770) in 10 ml ofether. After 10 minutes the solution is warmed to room temperature andthe solvent and excess diazomethane is removed in a stream of nitrogen.The residue is stirred at 55° C. in 15 ml of tetrahydrofuran containing5.75 ml of 2 M sulfuric acid for 30 minutes. The mixture is poured intowater and extracted with ether. The ether solution is washed withsaturated sodium bicarbonate, brine, and dried over magnesium sulfate.The ether is removed and the residue is chromatographed on a dry columnof silica gel eluting with hexane-ethyl acetate 3:2 to give the titlecompound.

EXAMPLE 772 Preparation of l-1,9-dioxo-15(S)-hydroxy-1-hydroxymethylprostane

A solution of 0.41 g of l-1,9-dioxo-15(S)-acetoxy-1-hydroxymethylprostane (Example 771) in 8 ml of methanol containing 1 ml of water and0.19 ml of concentrated sulfuric acid is refluxed for 5 hours. Themethanol is removed at reduced pressure and water and tetrahydrofuran isadded. The mixture is then refluxed for 1 hour. The mixture is pouredinto dilute sodium bicarbonate and extracted with ether. The ethersolution is washed with brine and dried over magnesium sulfate. Thesolvent is removed giving 0.34 g of the title compound.

EXAMPLE 773 Preparation of1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-20-nor-5-cis-13-trans-prostadiene,1-ethylene ketal

To a solution of 3.58 g (7.0 mmol) of1-iodo-4-triphenylmethoxy-1-trans-nonene (Example 112) in 8.0 ml ofether is added 8.9 ml of 1.6 M t-butyllithium solution (14.1 mmol) withstirring under argon at -78° C. The solution is allowed to warm to -30°C. over a 2 hour period. The solution is recooled to -78° C. and asolution of 7.0 mmol of copper pentyne and 2.9 ml ofhexamethylphosphorous triamide in 20 ml of ether is added. After 1 hour,3.28 g (7.0 mmol) of2-(8-dimethyl-t-butylsilyloxy-7-oxooct-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one,7-ethylene ketal (Example 280) in 5 ml of ether is added. The mixture isstirred at -30° C. for 2 hours and at 0° C. for 30 minutes. The mixtureis poured into 150 ml of saturated ammonium chloride and extracted withether. The ether solution is washed with dilute hydrochloric acid anddried over magnesium sulfate to give 6.0 g of an oil. A 3.0 g portion ofthis oil is stirred in 40 ml of tetrahydrofuran-0.6 N Hydrochloric acid5:1 for 5 hours at room temperature.

The mixture is poured into water and extracted with ether. The ether isremoved and the residue is heated in 70 ml of aceticacid-tetrahydrofuran-water 4:2:1 at 60° C. for 4 hours. The solvent isremoved at reduced pressure. Toluene is added and removed. The residueis chromatographed on a silica gel column eluting with ethyl acetategiving 0.1 g of the title compound.

EXAMPLE 774 Preparation of1,9-dioxo-11α,16-dihydroxy-16-methyl-1-hydroxymethyl-5-cis-13-trans-prostadiene,1-ethylene ketal

To a solution of 3.4 g (6.75 mmol) of(E)-4-trimethylsilyloxy-4-methyl-1-tri-n-butylstannyloctene (Example210b) in 3.5 ml of tetrahydrofuran with stirring at -78° C. under argonis added 2.8 ml (6.75 mmol) of 2.4 M n-butyllithium in hexane. Thesolution is maintained at -20° to -15° C. for 21/2 hours. A solution of0.89 g (6.75 mmol) of copper pentyne and 2.2 g of hexamethylphosphoroustriamide in 25 ml of ether is added at -78° C. After 1 hour, a solutionof 2.3 g (5.0 mmol) of2-(8-dimethyl-t-butylsilyloxy-7-oxooct-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one,7-ethyleneketal (Example 280) in 20 ml of ether is added. The solution is stirredat -45° C. for 30 minutes and at -45° to -20° C. over 30 minutes. To thesolution is added 3 ml of acetic acid followed by saturated ammoniumchloride. The mixture is poured into water and extracted with ether. Theether solution is washed with dilute hydrochloric acid, saturated sodiumbicarbonate and dried over magnesium sulfate. The solvent is removed andthe residue is stirred in 75 ml of tetrahydrofuran containing 15 ml of0.6 N hydrochloric acid and 1 ml of acetic acid at room temperature for5 hours. The solution is saturated with sodium chloride and extractedwith ethyl acetate. The ethyl acetate solution is washed with saturatedsodium bicarbonate and dried over magnesium sulfate. The solvent isremoved and the residue is chromatographed on a dry column of silica geleluting with ethyl acetate containing 0.5% acetic acid (1000 ml) to give0.65 g of the title compound.

EXAMPLES 775-868

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 40 areprepared by the indicated method from the indicated cyclopent-2-en-1one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers are listed in Table 40; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomers are alsoformed and are part of this invention.

                                      TABLE 40                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example   1,9-dioxo-1-hydroxymethylprostene             __________________________________________________________________________    775  773   280         49       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    -                                                                             methyl-16,16-trimethylene-20-nor-5-cis-                                       13-trans-prostadiene,1-ethylene ketal         776  773   280         50       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    -                                                                             methyl-16,16-trimethylene-20-methyl-5-                                        cis-13-trans-prostadiene,1-ethylene                                           ketal                                         777  773   280         51       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-ethyl-5-cis-13-                                      trans-prostadiene,1-ethylene ketal            778  773   280         13       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-13-trans-5-cis-                                         prostadiene,1-ethylene ketal                  779  774   280         210a     1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16-vinyl-5-cis-13-trans-prostadiene,1-                                     m                                                                             ethylene ketal                                780  774   280        199       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    ropyl-                                                                        20-ethyl-1-hydroxymethyl-5-cis-13-trans-                                      prostadiene,1-ethylene ketal                  781  774   280        201       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    20-                                                                           ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  782  774   280        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    ropyl-                                                                        1-hydroxymethyl-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                           783a                                                                              773   280         74       dl-erythro-1,9-dioxo-11α,15-dihydrox                                    y-16-                                                                         methoxy-1-hydroxymethyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                   783b                                                                              774   280         210c     1,9-dioxo-11α,16-dihydroxy-16-ethyl-                                    1-hy-                                                                         droxymethyl-5-cis-13-trans-prostadiene,1-                                     o                                                                             ethylene ketal                                784  773   280         77       dl-erythro-1,9-dioxo-11α,15-dihydrox                                    y-                                                                            16-ethoxy-1-hydroxymethyl-5-cis-13-                                           trans-prostadiene,1-ethylene ketal            785  773   280         83       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-1-hydroxymethyl-20-nor-5-cis-13-                                          trans-prostadiene,1-ethylene ketal            786  773   280         84       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-20-methyl-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene,1-ethylene ketal            787  773   280         85       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-20-ethyl-1-hydroxymethyl-5-cis-13-                                        trans-prostadiene,1-ethylene ketal            788  773   280         86       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-19-methyl-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene,1-ethylene ketal            789  773   280         87       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-1-hydroxymethyl-5-cis-13-trans-17-                                        trans-prostatriene,1-ethylene ketal           790  773   280         69       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          1-hydroxymethyl-5-cis-13-trans-hydroxy-                                       methyl,1-ethylene ketal                       791  773   280         88       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-nor-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                  792  773   280         76       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    droxy-                                                                        1-hydroxymethyl-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                          793  773   280         89       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-methyl-1-hydroxymethyl-5-cis-13-                                           trans-prostadiene,1-ethylene ketal            794  773   280         90       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-ethyl-1-hydroxymethyl-5-cis-13-trans-                                      prostadiene,1-ethylene ketal                  795  773   280         91       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          19-methyl-1-hydroxymethyl-5-cis-13-                                           trans-prostadiene,1-ethylene ketal            796  773   280         92       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          1-hydroxymethyl-5-cis-13-trans-17-trans-                                      prostatriene,1-ethylene ketal                 797  773   280        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-5-cis-13-trans-prostadiene,1-ethylene                                      ketal                                         798  773   280        108       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-19,20-dinor-5-cis-13-trans-prostadiene-                                    Z                                                                             1-ethylene ketal                              799  773   280        109       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-18,19,20-trinor-5-cis-13-trans-prosta-                                     1                                                                             diene,1-ethylene ketal                        800  773   280        110       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-20-nor-5-cis-13-trans-prostadiene,1-                                       ethylene ketal                                801  773   280        144       1,9-dioxo-11α,16-dihydroxy-17-methyl                                    -1-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          802  773   280        112       1,9-dioxo-11α,16-dihydroxy-20-methyl                                    -1-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          803  773   280        113       1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                    1-                                                                            hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          804  773   280         139a     1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -20-                                                                          ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  805  773   280        115       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-17-cis-5-cis-prostatriene,1-                                      ethylene ketal                                806  773   280        135       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          807  773   280        136       1,9-dioxo-11α,16-dihydroxy-17,17,20-                                    tri-                                                                          methyl-1-hydroxymethyl-5-cis-13-trans                                         prostadiene,1-ethylene ketal                  808  773   280        137       1,9-dioxo-11α,16-dihydroxy-16,20-dim                                    eth-                                                                          yl-1-hydroxymethyl-13-trans-5-cis-prosta-                                     l                                                                             diene,1-ethylene ketal                        809  773   280        138       1,9-dioxo-11α,16-dihydroxy-17,17-dim                                    eth-                                                                          yl-1-hydroxymethyl-5-cis-13-trans-prost-                                      adiene,1-ethylene ketal                       810  773   280        139       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-17-trans-5-cis-                                        prostatriene,1-ethylene ketal                 811  773   280        149       1,9-dioxo-11α,16-dihydroxy-20-methyl                                    -1-                                                                           hydroxymethyl-13-trans-17-trans-5-cis-                                        prostratriene,1-ethylene ketal                812  773   280        150       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          813  773   280        151       1,9-dioxo-11α,16-dihydroxy-17,20-dim                                    eth-                                                                          yl-1-hydroxymethl-5-cis-13-trans-prosta-                                      diene,1-ethylene ketal                        814  773   280        152       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-17-trans-5-cis-prostatriene-                                      1-ethylene ketal                              815  773   280        153       1,9-dioxo-11α,16(R)-dihydroxy-1-hydr                                    oxy-                                                                          methyl-5-cis-13-trans-prostadiene,1-eth-                                      ylene ketal                                   816  773   280        154       1,9-dioxo-11α,16(S)-dihydroxy-1-hydr                                    oxy-                                                                          methyl-5-cis-13-trans-prostadiene,1-eth-                                      ylene ketal                                   817  773   280         148a     1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                    1-                                                                            hydroxymethyl-5-cis-13-trans-17-trans-                                        prostatriene,1-ethylene ketal                 818  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-1-                                    hydroxymeth-                                                        ylmethoxy-1-trans-                                                                      yl-5-cis-13-trans-prostadiene,1-ethylene                            octene (U.S. Pat.                                                                       ketal                                                               No. 3,873,607).                                         819  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-20                                    -methyl-1                                                           ylmethoxy-1-trans-                                      hydroxymethyl-5-cis-13-trans-prostadiene,                                                           nonene (U.S. Pat.                                                                       1-ethylene ketal                                                    No. 3,873,607).                                         820  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-20                                    -ethyl-1-                                                           ylmethoxy-1-trans-                                                                      hydroxymethyl-5-cis-13-trans-prostadiene,                                     g                                                                   decene (U.S. Pat.                                                                       1-ethylene ketal                                                    No. 3,873,607).                                         821  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-dimeth-                                                         ylmethoxy-4,4-di-                                                                       yl-1-hydroxymethyl-5-cis-13-trans-prosta-                                     o                                                                   methyl-1-trans-                                                                         diene,1-ethylene ketal                                              octene (U.S. Pat.                                                             No. 3,873,607).                                         822  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-17                                    ,17-dimeth-                                                         ylmethoxy-5,5-di-                                                                       yl-5-cis-13-trans-prostadiene,1-ethylene                            methyl-1-trans-                                                                         ketal                                                               octene (U.S. Pat.                                                             No. 3,873,607).                                         823  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    -methyl-1-                                                          ylmethoxy-4-meth-                                                                       hydroxymethyl-5-cis-13-trans-prostadiene,                                     q                                                                   yl-1-trans-octene                                                                       1-ethylene ketal                                                    (U.S. Pat. No.                                                                3,876,690).                                             824  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    -ethyl-1-                                                           ylmethoxy-4-ethyl-                                                                      hydroxymethyl-5-cis-13-trans-prostadiene                            1-trans-octene                                                                          1-ethylene ketal                                                    (U.S. Pat. No.                                                                3,876,690).                                             825  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-17                                    ,20-tetra-                                                          ylmethoxy-3-cyclo-                                                                      nor-16-cyclopentyl-1-hydroxymethyl-5-cis-                                     2                                                                   pentyl-1-trans-                                                                         13-trans-prostadiene,1-ethylene ketal                               butene (U.S. Pat.                                                             No. 3,884,969).                                         826  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    ,20-pen-                                                            ylmethoxy-3-cyclo-                                                                      nor-15-cyclohexyl-1-hydroxymethyl-5-cis-                            hexyl-1-trans-                                                                          13-trans-prostadiene,1-ethylene ketal                               pentene (U.S. Pat.                                                            No. 3,884,969).                                         827  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-18                                    ,20-trinor-                                                         ylmethoxy-5-cyclo-                                                                      17-cyclohexyl-1-hydroxymethyl-5-cis-13-                             hexyl-1-trans-                                                                          trans-prostadiene,1-ethylene ketal                                  pentene (U.S. Pat.                                                            No. 3,884,969).                                         828  773   280        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-19                                    ,20-dinor-                                                          ylmethoxy-6-cyclo-                                                                      18-cyclopentyl-1-hydroxymethyl-5-cis-13-                            pentyl-1-trans-                                                                         trans-prostadiene,1-ethylene ketal                                  hexene (U.S. Pat.                                                             No. 3,884,969).                                         829  773   280        1-iodo-3-methyl-3-                                                                      1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-                                                            trimethylsilyl-                                                                         hydroxymethyl-5-cis-13-trans-prostadiene,                                     n                                                                   oxy-trans-1-octene                                                                      1-ethylene ketal                                                    (Example 125)                                           830  773   280        1-iodo-3-methyl-3-                                                                      1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-20-                                                         trimethylsilyl-                                                                         ethyl-1-hydroxymethyl-5-cis-13-trans-                               oxy-trans-1-decene                                                                      prostadiene,1-ethylene ketal                                        (Example 190a)                                          831  774   280        159       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-fluorophenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    u                                                                             ene ketal                                     832  774   280        186       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-phenoxy-1-hydroxymethyl-5-                                        cis-13-trans-prostadiene,1-ethylene                                           ketal                                         833  774   280        181       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-bromophenoxy-1-hydroxy-                                         methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    t                                                                             ene ketal                                     834  774   280        182       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-t-butylphenoxy-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    Z                                                                             ene ketal                                     835  774   280        183       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-methoxyphenoxy-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    6                                                                             ene ketal                                     836  774   280        184       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-chlorophenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene,1-                                          ethylene ketal                                837  774   280        180       1,9-dioxo-11α,15αdihydroxy-17,                                    18,19,20-                                                                     tetranor-m-trifluorophenoxy-1-hydroxy-                                        methyl-5-cis-13-trans-prostadiene,1-                                          ethylene ketal                                838  774   280        185       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-(3,4-dichlorophenoxy)-1-hy-                                       droxymethyl-5-cis-13-trans-prostadiene,1-                                     a                                                                             ethylene ketal                                839  774   280         186b     1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-phenyl-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene,1-ethylene ketal            840  774   280         186e     1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-(m-trifluoromethylphenyl)-1-hydr-                                      oxymethyl-5-cis-13-trans-prostadiene,1-                                       ethylene ketal                                841  774   280         186d     1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20,-tri-                                                                  nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                     x                                                                             5-cis-13-trans-prostadiene,1-ethylene                                         ketal                                         842  773   297        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-1-                                    hydroxymeth-                                                        ylmethoxy-1-trans-                                                                      yl-2-nor-5-cis-13-trans-prostadiene,1-                              octene (U.S. Pat.                                                                       ethylene ketal                                                      No. 3,873,607).                                         843  773   297        185       1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-1-                                                                    hydroxymethyl-2-nor-5-cis-13-trans-prost-                                     .                                                                             adiene,1-ethylene ketal                       844  773   297        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-dimeth-                                                         ylmethoxy-5,5-di-                                                                       yl-1-hydroxymethyl-2-nor-5-cis-13-trans-                            methyl octene                                                                           prostadiene,1-ethylene ketal                                        (U.S. Pat. No.                                                                3,873,607).                                             845  773   297         13       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-tri-                                                                      methylene-1-hydroxymethyl-2-nor-5-cis-                                        13-trans-prostadiene,1-ethylene ketal         846  773   297         76       erythro-1,9-dioxo-11α,15α,16-t                                    rihydroxy-                                                                    1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  847  773   297         69       threo-1,9-dioxo-11α,15α,16-tri                                    hydroxy-1-                                                                    hydroxymethyl-2-nor-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                  848  773   297         74       erythro-1,9-dioxo-11α,15α,16-d                                    ihydroxy-16-                                                                  methoxy-1-hydroxymethyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                  849  773   297        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-2-nor-5-cis-13-trans-prostadiene,1-                                        ethylene ketal                                850  773   297        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-2-nor-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                  851  773   297        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-2-nor-5-cis-13-trans-17-                                        trans-prostadiene,1-ethylene ketal            852  774   297        186       1,9-dioxo-11α,15α-dihydroxy-2,                                    17,18,19,-                                                                    20-pentanor-16-phenoxy-1-hydroxymethyl-5-                                     Z                                                                             cis-13-trans-prostadiene,1-ethylene                                           ketal                                         853  774   297        180       1,9-dioxo-11α,15α-dihydroxy-2,                                    17,18,19,-                                                                    20-pentanor-16-m-trifluromethylphenoxy-                                       1-hydroxymethyl-5-cis-13-trans-prostadi--                                     8  ene,1-ethylene ketal                       854  773   297        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    1-hy-                                                                         droxymethyl-2-nor-5-cis-13-trans-prosta-                                      diene,1-ethylene ketal                        855  774   297        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    ropyl-                                                                        1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  856  774   297         186b     1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-phenyl-1-hydroxymethyl-5-                                         cis-13-trans-prostadiene,1-ethylene                                           ketal                                         857  773   297         186e     1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-(m-trifluorophenyl)-1-hydr-                                       oxymethyl-5-cis-13-trans-prostadiene,1-                                       ethylene ketal                                858  773   297         186d     1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-(p-methoxyphenyl)-1-hydroxy-                                      methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    n                                                                             ene ketal                                     859  773   310        125       1,9-dioxo-15-hydroxy-15-methyl-1-hydroxy-                                     .                                                                             methyl-2-nor-13-trans-prostene,1-ethylene                                     Z                                                                             ketal                                         860  773   298        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           homo-1-hydroxymethyl-5-cis-13-trans-                                          prostadiene,1-ethylene ketal                  861  773   298        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           homo-1-hydroxymethyl-5-cis-13-trans-17-                                       trans-prostatriene,1-ethylene ketal           862  774   298        186       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-phenoxy-1-hydroxymethyl-5-                                        cis-13-trans-prostadiene,1-ethylene                                           ketal                                         863  774   298        180       1,9-dioxo-11α,15α                                                 -dihydroxy-17,18,19,20-                                                       tetranor-16-m-trifluoromethylphenoxy-1-                                       hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          864  773   298        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    1-homo-                                                                       1-hydroxymethyl-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                          865  774   298        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    rop-                                                                          yl-1-homo-1-hydroxymethyl-5-cis-13-trans-                                     s                                                                             prostadiene,1-ethylene ketal                  866  774   298         186b     1,9-dioxo-11α,15α-dihydroxy-1-                                    homo-18,19-                                                                   20-trinor-17-phenyl-1-hydroxymethyl-5-cis-                                    r                                                                             13-trans-prostadiene,1-ethylene ketal         867  773   298         186e     1,9-dioxo-11α,15α-dihydroxy-1-                                    homo-18,19,-                                                                  20-trinor-17-(m-trifluorophenyl)-1-hydr-                                      oxymethyl-13-trans-5-cis-prostadiene,1-                                       ethylene ketal                                868  773   298         186d     1,9-dioxo-11α,15α-dihydroxy-1-                                    homo-18,19-                                                                   20-trinor-17-(p-methoxyphenyl)-1-hydroxy-                                     t                                                                             methyl-13-trans-5-cis-prostadiene,1-ethyl-                                    .                                                                             ene ketal                                     __________________________________________________________________________

EXAMPLES 869-891

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 41 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table41. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymmetric carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 41                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-1-hydroxymethylprostene and           Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    869  773   280        246     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-tetramethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                    870  774   280        245     nat-(and ent)-1,9-dioxo-11α,16-dihydro                                  xy-                                                                           16,17-tetramethylene-18,19,20-trinor-1-                                       hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                            871  773   280        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  0                                                                             hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                            872  773   280        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  +                                                                             hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            873  773   280        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  Z                                                                             hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            874  773   280        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-trimethylene-17,18,19,20-tetranor-                                      1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene,1-ethylene ketal                            875  774   280        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-pentamethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-5-cis-prosta-                                    diene,1-ethylene ketal                          876  773   280        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-dimethylene-1-h                                  y-                                                                            droxymethyl-13-trans-5-cis-prostadiene,1-                                     ethylene ketal                                  877  773   280        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-dimethylene-1-h                                  y-                                                                            droxymethyl-13-trans-5-cis-prostadiene,1-                                     ethylene ketal                                  878  773   280        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-tetramethylene-                                  -                                                                             hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            879  773   280        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-tetramethylene-                                  1-                                                                            hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            880  774   280        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene,1-ethylene ketal                    881  774   280        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene,1-ethylene ketal                    882  773   280        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene,1-ethylene ketal                            883  773   280        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-1-                                     hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            884  774   280        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene,1-ethylene ketal                            885  774   280        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene,1-ethylene ketal                            886  773   280        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene,1-ethylene ketal                    887  773   280        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-5-cis-                                      prostadiene,1-ethylene ketal                    888  774   280        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-5-cis-                                        prostadiene,1-ethylene ketal                    889  774   280        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-5-cis-                                        prostadiene,1-ethylene ketal                    890  774   280        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene,1-ethylene ketal                         891  774   280        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene,1-ethylene ketal                         __________________________________________________________________________

EXAMPLES 892-975

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-hydroxymethyl prostene derivatives shown in Table 42 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers are listed in Table 42; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomers are alsoformed and are part of this invention.

In those cases where the initial conjugate-addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 42                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example   1,9-dioxo-1-hydroxymethylprostene             __________________________________________________________________________    892  773   309         49       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-nor-13-trans-                                        prostene,1-ethylene ketal                     893  773   309         50       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-methyl-13-trans-                                     .                                                                             prostene,1-ethylene ketal                     894  773   309         51       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-20-ethyl-13-trans-                                      prostene,1-ethylene ketal                     895  774   309        193       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    rop-                                                                          yl-20-ethyl-1-hydroxymethyl-13-trans-                                         prostene,1-ethylene ketal                     896  774   309        195       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    20-                                                                           ethyl-1-hydroxymethyl-13-trans-prostene,                                      1-ethylene ketal                              897  774   309        192       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    rop-                                                                          yl-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                898  773   309         13       1,9-dioxo-11α,15-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16,16-trimethylene-13-trans-prostene,-                                     i                                                                             1-ethylene ketal                              899  773   309         210a     1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-16-vinyl-13-trans-prostene,1-ethylene                                      ketal                                         900  773   309         74       dl-erythro-1,9-dioxo-11α,15-dihydrox                                    y-16-                                                                         methoxy-1-hydroxymethyl-13-trans-prost-                                       ene,1-ethylene ketal                          901  773   309         77       dl-erythro-1,9-dioxo-11α,15-dihydrox                                    y-16-                                                                         ethoxy-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                          902  773   309         83       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-1-hydroxymethyl-20-nor-13-trans-                                          prostene,1-ethylene ketal                     903  773   309         84       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-1-hydroxymethyl-20-methyl-13-trans-                                       prostene,1-ethylene ketal                     904  773   309         85       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-1-hydroxymethyl-20-ethyl-13-trans-                                        prostene,1-ethylene ketal                     905  773   309         86       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dro-                                                                          oxy-19-methyl-1-hydroxymethyl-13-trans-                                       prostene,1-ethylene ketal                     906  773   309         87       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-13-trans-17-trans-prostadiene,1-eth-                                      ylene ketal                                   907  773   309         69       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          1-hydroxymethyl-13-trans-prostene,1-                                          ethylene ketal                                908  773   309         88       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-nor-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                          909  773   309         76       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    dr-                                                                           oxy-1-hydroxymethyl-13-trans-prostene,1-                                      ethylene ketal                                910  773   309         89       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-methyl-1-hydroxymethyl-13-trans-                                           prostene,1-ethylene ketal                     911  773   309         90       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          20-ethyl-1-hydroxymethyl-13-trans-prost-                                      ene,1-ethylene ketal                          912  773   309         91       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          19-methyl-1-hydroxymethyl-13-trans-                                           prostene,1-ethylene ketal                     913  773   309         92       dl-threo-1,9-dioxo-11α,15,16-trihydr                                    oxy-                                                                          1-hydroxymethyl-13-trans-17-trans-                                            prostadiene,1-ethylene ketal                  914  773   309        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-prostene,1-ethylene ketal         915  773   309        108       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-19,20-dinor-13-trans-prostene,1-ethyl-                                     .                                                                             ene ketal                                     916  773   309        109       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-18,19,20-trinor-13-trans-prostene,1-                                       ethylene ketal                                917  773   309        110       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-20-nor-13-trans-prostene,1-ethylene                                        ketal                                         918  773   309        144       1,9-dioxo-11α,16-dihydroxy-17-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                     919  773   309        112       1,9-dioxo-11α,16-dihydroxy-20-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                     920  773   309        113       1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                    1-                                                                            hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                     921  773   309         139a     1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -20-                                                                          ethyl-1-hydroxymethyl-13-trans-prostene,                                      1-ethylene ketal                              922  773   309        115       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-17-cis-prostadiene,1-ethylene                                     e                                                                             ketal                                         923  773   309        135       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                     924  773   309        136       1,9-dioxo-11α,16-dihydroxy-17,17,20-                                    tri-                                                                          methyl-1-hydroxymethyl-13-trans-prostene,                                     8                                                                             1-ethylene ketal                              925  773   309        137       1,9-dioxo-11α,16-dihydroxy-16,20-dim                                    eth-                                                                          yl-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                926  773   309        138       1,9-dioxo-11α,16-dihydroxy-17,17-dim                                    eth-                                                                          yl-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                927  773   309        139       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-17-trans-prosta-                                       diene,1-ethylene ketal                        928  773   309        149       1,9-dioxo-11α,16-dihydroxy-20-methyl                                    -1-                                                                           hydroxymethyl-13-trans-17-trans-prosta-                                       diene,1-ethylene ketal                        929  773   309        150       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                     930  773   309        151       1,9-dioxo-11α,16-dihydroxy-17,20-dim                                    eth-                                                                          y1-1-hydroxymethyl-13-trans-prostene,1-                                       ethylene ketal                                931  773   309        152       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-13-trans-17-trans-prostadiene,1-ethyl-                                     9                                                                             ene ketal                                     932  773   309        153       1,9-dioxo-11α,16(R)-dihydroxy-1-hydr                                    oxy-                                                                          methyl-13-trans-prostene,1-ethylene                                           ketal                                         933  773   309        154       1,9-dioxo-11α,16(S)-dihydroxy-1-hydr                                    oxy-                                                                          methyl-13-trans-prostene,1-ethylene                                           ketal                                         934  773   309         148a     1,9-dioxo-11α,16-dihydroxy-20-ethyl-                                    1-hy-                                                                         droxymethyl-13-trans-17-trans-prostadi-                                       ene,1-ethylene ketal                          935  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-1-                                    hydroxy-                                                            ylmethoxy-1-trans-                                                                      methyl-13-trans-prostadiene,1-ethylene                              octene (U.S. Pat.                                                                       ketal                                                               No. 3,873,607).                                         936  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-20                                    -methyl-1-                                                          ylmethoxy-1-trans-                                                                      hydroxymethyl-13-trans-prostene,1-ethyl-                            nonene (U.S. Pat.                                                                       ene ketal                                                           No. 3,873,607).                                         937  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-20                                    -ethyl-1-                                                           ylmethoxy-1-trans-                                                                      hydroxymethyl-13-trans-prostene,1-ethyl-                            decene (U.S. Pat.                                                                       ene ketal                                                           No. 3,873,607).                                         938  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-dimeth-                                                         ylmethoxy-4,4-di-                                                                       yl-1-hydroxymethyl-13-trans-prostene,1-                             methyl-1-trans-                                                                         ethylene ketal                                                      octene (U.S. Pat.                                                             No. 3,873,607).                                         939  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-17                                    ,17-dimeth-                                                         ylmethoxy-5,5-di-                                                                       yl-1-hydroxymethyl-13-trans-prostene,1-                             methyl-1-trans-                                                                         ethylene ketal                                                      octene (U.S. Pat.                                                             No. 3,873,607).                                         940  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    -methyl-1-                                                          ylmethoxy-4-meth-                                                                       hydroxymethyl-13-trans-prostene,1-ethyl-                            yl-1-trans-octene                                                                       ene ketal                                                           (U.S. Pat. No.                                                                3,876,690).                                             941  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    -ethyl-1-                                                           ylmethoxy-4-ethyl-                                                                      hydroxymethyl-13-trans-prostene,1-ethyl-                            1-trans-octene                                                                          ene ketal                                                           (U.S. Pat. No.                                                                3,876,690).                                             942  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-17                                    ,20-tetra-                                                          ylmethoxy-4-cyclo-                                                                      nor-16-cyclopentyl-1-hydroxymethyl-13-                              pentyl-1-trans-                                                                         trans-prostene,1-ethylene ketal                                     butene(U.S. Pat.                                                              No. 3,884,969).                                         943  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    ,20-penta-                                                          ylmethoxy-3-cyclo-                                                                      nor-15-cyclohexyl-1-hydroxymethyl-13-                               hexyl-1-trans-                                                                          trans-prostene,1-ethylene ketal                                     pentene (U.S. Pat.                                                            No. 3,884,969).                                         944  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-18                                    ,20-trinor-                                                         ylmethoxy-5-cyclo-                                                                      17-cyclohexyl-1-hydroxymethyl-13-trans-                             hexyl-1-trans-                                                                          prostene,1-ethylene ketal                                           pentene (U.S. Pat.                                                            No. 3,884,969).                                         945  773   309        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-19                                    ,20-dinor-                                                          ylmethoxy-6-cyclo-                                                                      18-cyclopentyl-1-hydroxymethyl-13-trans-                            pentyl-1-trans-                                                                         prostene,1-ethylene ketal                                           hexene (U.S. Pat.                                                             No. 3,884,969).                                         946  773   309        1-iodo-3-methyl-                                                                        1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-1-                                                          3-trimethylsilyl-                                                                       hydroxymethyl-13-trans-prostene,1-ethyl-                            oxy-trans-1-octene                                                                      ene ketal                                                           (Example 125)                                           947  773   309        1-iodo-3-methyl-                                                                        1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-20-                                                         3-trimethylsilyl-                                                                       ethyl-1-hydroxymethyl-13-trans-prostene-                            oxy-trans-1-decene                                                                      1-ethylene ketal                                                    (Example 190a)                                          948  774   309        159       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-fluorophenoxy-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene                                           ketal                                         949  774   309        186       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-phenoxy-1-hydroxymethyl-13-                                       trans-prostene,1-ethylene ketal               950  774   309        181       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-bromophenoxy-1-hydroxy-                                         methyl-13-trans-prostene,1-ethylene                                           ketal                                         951  774   309        182       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-t-butylphenoxy-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene                                           ketal                                         952  774   309        183       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-methoxyphenoxy-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene                                           ketal                                         953  774   309        184       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-p-chlorophenoxy-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene                                           ketal                                         954  774   309        180       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-m-trifluorophenoxy-1-hydroxy-                                        methyl-13-trans-prostene,1-ethylene                                           ketal                                         955  774   309        185       1,9-dioxo-11α,15α-dihydroxy-17                                    ,18,19,20-                                                                    tetranor-16-(3,4-dichlorophenoxy)-1-hy-                                       droxymethyl-13-trans-prostene,1-ethylene                                      ketal                                         956  774   309         186b     1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-phenyl-1-hydroxymethyl-13-trans-                                       prostene,1-ethylene ketal                     957  774   309         186e     1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-                                                                       nor-17-(m-trifluoromethylphenyl)-1-hydr-                                      oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                         958  774   309         186d     1,9-dioxo-11α,15α-dihydroxy-18                                    ,19,20-tri-                                                                   nor-17-(p-methoxyphenyl)-1-hydroxymethyl-                                     Z                                                                             13-trans-prostene,1-ethylene ketal            959  773   312        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-1-                                    hydroxy-                                                            ylmethoxy-1-trans-                                                                      methyl-2-nor-13-trans-prostadiene,1-                                octene (U.S. Pat.                                                                       ethylene ketal                                                      No. 3,873,607).                                         960  773   312        185       1,9-dioxo-11α,15α-dihydroxy-15                                    -methyl-1-                                                                    hydroxymethyl-2-nor-13-trans-prostene,1-                                      ethylene ketal                                961  773   312        1-iodo-3-triphen-                                                                       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-dimeth-                                                         ylmethoxy-5,5-di-                                                                       yl-1-hydroxymethyl-2-nor-13-trans-prost-                            methyl-octene                                                                           ene,1-ethylene ketal                                                (U.S. Pat. No.                                                                3,873,607).                                             962  773   312         13       1,9-dioxo-11α,15α-dihydroxy-16                                    ,16-tri-                                                                      methylene-1-hydroxymethyl-2-nor-13-trans-                                     .                                                                             prostene,1-ethylene ketal                     963  773   312         76       erythro-1,9-dioxo-11α,15α,16-t                                    rihydroxy-                                                                    1-hydroxymethyl-2-nor-13-trans-prostene,                                      1-ethylene ketal                              964  773   312         69       threo-1,9-dioxo-11α,15α,16-tri                                    hydroxy-1-                                                                    hydroxymethyl-2-nor-13-trans-prostene,-                                       1-ethylene ketal                              965  773   312         74       erythro-1,9-dioxo-11α,15α-dihy                                    droxy-16-                                                                     methoxy-1-hydroxymethyl-2-nor-13-trans-                                       prostene,1-ethylene ketal                     966  773   312        107       1,9-dioxo-11α,16-dihydroxy-1-hydroxy                                    meth-                                                                         yl-2-nor-13-trans-prostene,1-ethylene                                         ketal                                         967  773   312        130       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-2-nor-13-trans-prostene,-                                       1-ethylene ketal                              968  773   312        134       1,9-dioxo-11α,16-dihydroxy-16-methyl                                    -1-                                                                           hydroxymethyl-2-nor-13-trans-17-trans-                                        prostadiene,1-ethylene ketal                  969  774   312        186       1,9-dioxo-11α,15α-dihydroxy-2,                                    17,18,19,-                                                                    20-pentanor-16-phenoxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal            970  774   312        180       1,9-dioxo-11α,15α-dihydroxy-2,                                    17,18,19,-                                                                    20-pentanor-16-m-trifluoromethylphenoxy-                                      1-hydroxymethyl-13-trans-prostene,1-eth-                                      ylene ketal                                   971  773   312        194       1,9-dioxo-11α,16-dihydroxy-16-vinyl-                                    1-hy-                                                                         droxymethyl-2-nor-13-trans-prostene,1-                                        ethylene ketal                                972  774   312        198       1,9-dioxo-11α,16-dihydroxy-16-cyclop                                    rop-                                                                          yl-1-hydroxymethyl-2-nor-13-trans-                                            prostene,1-ethylene ketal                     973  774   312         186b     1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-phenyl-1-hydroxymethyl-13-                                        trans-prostene,1-ethylene ketal               974  773   312         186e     1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-(m-trifluorophenyl)-1-hydr-                                       oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                         975  773   312         186d     1,9-dioxo-11α,15α-dihydroxy-2,                                    18,19,20-                                                                     tetranor-17-(p-methoxyphenyl)-1-hydroxy-                                      methyl-13-trans-prostene,1-ethylene           __________________________________________________________________________                                    ketal                                     

EXAMPLES 976-998

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 43 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table43. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymmetri carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their components enantiomers.

                                      TABLE 43                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-hydroxymethylprostene and             Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    976  773   309        246     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-tetramethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-prostene,1-                                      ethylene ketal                                  977  774   309        245     nat-(and ent)-1,9-dioxo-11α,                                            16-dihydroxy-                                                                 16,17-tetramethylene-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                       978  773   309        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  N                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                       979  773   309        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  O                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                       980  773   309        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-1-                                  f                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                       981  773   309        247     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-trimethylene-17,18,19,20-tetranor-                                      1-hydroxymethyl-13-trans-prostene,1-eth-                                      ylene ketal                                     982  774   309        248     nat-(and ent)-1,9-dioxo-11α,15-dihydro                                  xy-                                                                           15,16-pentamethylene-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-prostene,1-                                      ethylene ketal                                  983  773   309        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-dimethylene-1-h                                  y-                                                                            droxymethyl-13-trans-prostene,1-ethylene                                      ketal                                           984  773   309        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-dimethylene-1-h                                  y-                                                                            droxymethyl-13-trans-prostene,1-ethylene                                      ketal                                           985  773   309        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-                                    hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                       986  773   309        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-tetramethylene-                                  1-                                                                            hydroxymethyl-13-trans-prostene,1-ethyl-                                      ene ketal                                       987  774   309        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-prost-                                      ene,1-ethylene ketal                            988  774   309        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-17,18,19,20-                                       tetranor-1-hydroxymethyl-13-trans-prost-                                      ene,1-ethylene ketal                            989  773   309        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene,1-                                          ethylene ketal                                  990  773   309        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (4-fluorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene,1-                                          ethylene ketal                                  991  774   309        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-16                                  -                                                                             (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene,1-                                          ethylene ketal                                  992  774   309        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      11α,15-dihydroxy-15,16-trimethylene-                                    (3-chlorophenoxy)-17,18,19,20-tetranor-                                       1-hydroxymethyl-13-trans-prostene,1-                                          ethylene ketal                                  993  773   309        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-prost-                                      ene,1-ethylene ketal                            994  773   309        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      11α,15-dihydroxy-15,17-trimethylene-19                                  ,-                                                                            20-dinor-1-hydroxymethyl-13-trans-prost-                                      ene,1-ethylene ketal                            995  774   309        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                            996  774   309        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-20                                  -                                                                             methyl-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                            997  774   309        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-prostene,1-                                      ethylene ketal                                  998  774   309        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      11α,16-dihydroxy-16,17-trimethylene-16                                  -                                                                             (3-trifluoromethylphenoxy)-18,19,20-tri-                                      nor-1-hydroxymethyl-13-trans-prostene-                                        ethylene ketal                                  __________________________________________________________________________

EXAMPLES 999-1082

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 44 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers are listed in Table 44; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomer is also formedand is part of this invention.

In those cases where the initial conjugate-addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 44                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example   1,9-dioxo-1-hydroxymethylprostene             __________________________________________________________________________     999 773   314         49       1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     o                                                                             16-trimethylene-20-nor-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                  1000 773   314         50       1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     r                                                                             16-trimethylene-20-methyl-5-cis-13-trans-                                     e                                                                             prostadiene,1-ethylene ketal                  1001 773   314         51       1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     .                                                                             16-trimethylene-20-ethyl-5-cis-13-trans-                                      prostadiene,1-ethylene ketal                  1002 774   314        193       1,9-dioxo-16-hydroxy-16-cyclopropyl-20-                                       ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  1003 774   314        195       1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1-                                     Z                                                                             hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                          1004 774   314        192       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                     4                                                                             droxymethyl-5-cis-13-trans-prostadiene,1-                                     5                                                                             ethylene ketal                                1005 773   314         13       1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     .                                                                             16-trimethylene-13-trans-5-cis-prostadi-                                      ene,1-ethylene ketal                          1006 774   314         210a     1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-                                      vinyl-5-cis-13-trans-prostadiene,1-eth-                                       ylene ketal                                   1007 773   314         74       dl-erythro-1,9-dioxo-15-hydroxy-16-meth-                                      oxy-1-hydroxymethyl-5-cis-13-trans-prost-                                     B                                                                             adiene,1-ethylene ketal                       1008 773   314         77       dl-erythro-1,9-dioxo-15-hydroxy-16-eth-                                       oxy-1-hydroxymethyl-5-cis-13-trans-prost-                                     E                                                                             adiene,1-ethylene ketal                       1009 773   314         83       dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-2-nor-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                  1010 773   314         84       dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-methyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                  1011 773   314         85       dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-ethyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                  1012 773   314         86       dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-19-methyl-5-cis-13-trans-                                       prostadiene,1-ethylene ketal                  1013 773   314         87       dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-5-cis-13-trans-17-trans-                                        prostratiene,1-ethylene ketal                 1014 773   314         69       dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      droxymethyl-5-cis-13-trans-prostadiene,1-                                     C                                                                             ethylene ketal                                1015 773   314         88       dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        nor-1-hydroxymethyl-5-cis-13-trans-                                           prostadiene,1-ethylene ketal                  1016 773   314         76       dl-erythro-1,9-dioxo-11α,15,16-trihy                                    droxy- -    1-hydroxymethyl-5-cis-13-trans                                    -prostadi-                                                                    ene,1-ethylene ketal                          1017 773   314         89       dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                  1018 773   314         90       dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        ethyl-1-hydroxymethyl-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  1019 773   314         91       dl-threo-1,9-dioxo-15,16-dihydroxy-19-                                        methyl-1-hydroxymethyl-5-cis-13-trans-                                        prostadiene,1-ethylene ketal                  1020 773   314         92       dl-threo-1,9-dioxo-15,16-dihydroxy-1-                                         hydroxymethyl-5-cis-13-trans-17-trans-                                        prostatriene,1-ethylene ketal                 1021 773   314        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-5-                                       cis-3-trans-prostadiene,1-ethylene ketal      1022 773   314        108       1,9-dioxo-16-hydroxy-1-hydroxymethyl-19-                                      20-dinor-5-cis-13-trans-prostadiene,1-                                        ethylene ketal                                1023 773   314        109       1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                     A                                                                             19,20-trinor-5-cis-13-trans-prostadiene,1-                                    U                                                                             ethylene ketal                                1024 773   314        110       1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                      nor-5-cis-13-trans-prostadiene,1-ethyl-                                       ene ketal                                     1025 773   314        144       1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy-                                     S                                                                             methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    E                                                                             ene ketal                                     1026 773   314        112       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     .                                                                             methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    Z                                                                             ene ketal                                     1027 773   314        113       1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    4                                                                             ene ketal                                     1028 773   314         139a     1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                      1-hydroxymethyl-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                          1029 773   314        115       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      trans-17-cis-5-cis-prostatriene,1-ethyl-                                      ene ketal                                     1030 773   314        135       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     6                                                                             methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    .                                                                             ene ketal                                     1031 773   314        136       1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                      1-hydroxymethyl-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                          1032 773   314        137       1,9-dioxo-16-hydroxy-16,20-dimethyl-1-hy-                                     m                                                                             droxymethyl-13-trans-5-cis-prostadiene,1-                                     u                                                                             ethylene ketal                                1033 773   314        138       1,9-dioxo-16-hydroxy-17,17-dimethyl-1-hy-                                     s                                                                             droxymethyl-5-cis-13-trans-prostadiene,1-                                     i                                                                             ethylene ketal                                1034 773   314        139       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     c                                                                             methyl-13-trans-17-trans-5-cis-prostatri-                                     -                                                                             ene,1-ethylene ketal                          1035 773   314        149       1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     s                                                                             methyl-13-trans-17-trans-5-cis-prostatri-                                     h                                                                             ene,1-ethylene ketal                          1036 773   314        150       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     a                                                                             methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    r                                                                             ene ketal                                     1037 773   314        151       1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                     p                                                                             droxymethyl-5-cis-13-trans-prostadiene,1-                                     .                                                                             ethylene ketal                                1038 773   314        152       1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      trans-17-trans-5-cis-prostatriene,1-eth-                                      ylene ketal                                   1039 773   314        153       1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl-                                      5-cis-13-trans-prostadiene,1-ethylene                                         -    ketal                                    1040 773   314        154       1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                      5-cis-13-trans-prostadiene,1-ethylene                                         ketal                                         1041 773   314         148a     1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      methyl-5-cis-13-trans-17-trans-prostatri-                                     Z                                                                             ene,1-ethylene ketal                          1042 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-1-hydroxymethy                                    l-5-                                                                ylmethoxy-1-trans-                                                                      cis-13-trans-prostadiene,1-ethylene                                 octene (U,S. Pat.                                                                       ketal                                                               No. 3,873,607).                                         1043 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-20-methyl-1-hy                                    dr-                                                                 ylmethoxy-1-trans-                                                                      oxymethyl-5-cis-13-trans-prostadiene,1-                             nonene (U.S. Pat.                                                                       ethylene ketal                                                      No. 3,873,607).                                         1044 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-20-ethyl-1-hyd                                    roxy-                                                               ylmethoxy-1-trans-                                                                      methyl-5-cis-13-trans-prostadiene,1-eth-                            decene (U.S. Pat.                                                                       ylene ketal                                                         No. 3,873,607).                                         1045 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16,16-dimethyl                                    -1-                                                                 ylmethoxy-4,4-di-                                                                       hydroxymethyl-5-cis-13-trans-prostadi-                              methyl-1-trans-                                                                         ene,1-ethylene ketal                                                octene (U.S. Pat.                                                             No. 3,873,607).                                         1046 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-17,17-dimethyl                                    -1-                                                                 ylmethoxy-5,5-di-                                                                       hydroxymethyl-5-cis-13-trans-prostadi-                              methyl-1-trans-                                                                         ene,1-ethylene ketal                                                octene (U.S. Pat.                                                             No. 3,873,607).                                         1047 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16-methyl-1-hy                                    dr-                                                                 ylmethoxy-4-meth-                                                                       oxymethyl-5-cis-13-trans-prostadiene,1-                             yl-1-trans-octene                                                                       ethylene ketal                                                      (U.S. Pat. No.                                                                3,876,690).                                             1048 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16-ethyl-1-hyd                                    roxy-                                                               ylmethoxy-4-ethyl-                                                                      methyl-5-cis-13-trans-prostadiene,1-eth-                            1-trans-octene                                                                          ylene ketal                                                         (U.S. Pat. No.                                                                3,876,690).                                             1049 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-17,20-tetranor                                    -16-                                                                ylmethoxy-4-cyclo-                                                                      cyclopentyl-1-hydroxymethyl-5-cis-13-                               pentyl-1-trans-                                                                         trans-prostadiene,1-ethylene ketal                                  butene (U.S. Pat.                                                             No. 3,884,969).                                         1050 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16,20-pentanor                                    -15-                                                                ylmethoxy-3-cyclo-                                                                      cyclohexyl-1-hydroxymethyl-5-cis-13-                                hexyl-1-trans-                                                                          trans-prostadiene,1-ethylene ketal                                  pentene (U.S. Pat.                                                            No. 3,884,969).                                         1051 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-18,20-trinor-1                                    7-                                                                  ylmethoxy-5-cyclo-                                                                      cyclohexyl-1-hydroxymethyl-5-cis-13-                                hexyl-1-trans-                                                                          trans-prostadiene,1-ethylene ketal                                  pentene (U.S. Pat.                                                            No. 3,884,969).                                         1052 773   314        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-19,20-dinor-18                                    -                                                                   ylmethoxy-6-cyclo-                                                                      cyclopentyl-1-hydroxymethyl-5-cis-13-                               pentyl-1-trans-                                                                         trans-protadiene,1-ethylene ketal                                   hexene (U.S. Pat.                                                             No. 3,884,969).                                         1053 773   314        1-iodo-3-methyl-3-                                                                      1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                    dr-                                                                 trimethylsilyl-                                                                         oxymethyl-5-cis-13-trans-prostadiene,1-                             oxy-trans-1-octene                                                                      ethylene ketal                                                      (Example 125)                                           1054 773   314        1-iodo-3-methyl-3-                                                                      1,9-dioxo-15α-hydroxy-15-methyl-20-e                                    thyl-                                                               trimethylsilyl-                                                                         1-hydroxymethyl-5-cis-13-trans-prostadi-                            oxy-trans-1-decene                                                                      ene,1-ethylene ketal                                                (Example 190a)                                          1055 774   314        159       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-fluorophenoxy-1-hydroxymethyl-5-                                     t                                                                             cis-13-trans-prostadiene,1-ethylene                                           ketal                                         1056 774   314        186       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-phenoxy-1-hydroxymethyl-5-cis-13-                                      trans-prostadiene,1-ethylene ketal            1057 774   314        181       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-bromophenoxy-1-hydroxymethyl-5-                                      cis-13-trans-prostadiene,1-ethylene                                           ketal                                         1058 774   314        182       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-6-p-t-butylphenoxy-1-hydroxymethyl-                                       5-cis-13-trans-prostadiene,1-ethylene                                         ketal                                         1059 774   314        183       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                      5-cis-13-trans-prostadiene,1-ethylene                                         ketal                                         1060 774   314        184       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-p-chlorophenoxy-1-hydroxymethyl-5-                                     Z                                                                             cis-13-trans-prostadiene,1-ethylene                                           ketal                                         1061 774   314        180       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-m-trifluorophenoxy-1-hydroxymethyl-5-                                     9                                                                             cis-13-trans-prostadiene,1-ethylene                                           ketal                                         1062 774   314        185       1,9-dioxo-15α-hydroxy-17,18,19,20-te                                    tra-                                                                          nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                       methyl-5-cis-13-trans-prostadiene,1-ethyl-                                    N                                                                             ene ketal                                     1063 774   314         186b     1,9-dioxo-15α-hydroxy-18,19,20-trino                                    r-                                                                            17-phenyl-1-hydroxymethyl-5-cis-13-trans-                                     Z                                                                             prostadiene,1-ethylene ketal                  1064 774   314         186e     1,9-dioxo-15α-hydroxy-18,19,20-trino                                    r-17-                                                                         (m-trifluoromethylphenyl)-1-hydroxymeth-                                      yl-5-cis-13-trans-prostadiene,1-ethylene                                      ketal                                         1065 774   314         186d     1,9-dioxo-15α-hydroxy-18,19,20-trino                                    r-17-                                                                         (p-methoxyphenyl)-1-hydroxymethyl-5-cis-                                      13-trans-prostadiene,1-ethylene ketal         1066 773   315        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-1-hydroxymethy                                    l-2-                                                                ylmethoxy-1-trans-                                                                      nor-5-cis-13-trans-prostadiene,1-ethyl-                             octene (U.S. Pat.                                                                       ene ketal                                                           No. 3,873,607).                                         1067 773   315        185       1,9-dioxo-15α-hydroxy-15-methyl-1-hy                                    droxy-                                                                        methyl-2-nor-5-cis-13-trans-prostadiene,-                                     b                                                                             1-ethylene ketal                              1068 773   315        1-iodo-3-triphen-                                                                       1,9-dioxo-15α-hydroxy-16,16-dimethyl                                    -1-hy-                                                              ylmethoxy-5,5-di-                                                                       droxymethyl-2-nor-5-cis-13-trans-prostadi-                                    .                                                                   methyl-octene                                                                           ene,1-ethylene ketal                                                (U.S. Pat. No.                                                                3,873,607).                                             1069 773   315         13       1,9-dioxo-15α-hydroxy-16,16-trimethy                                    lene-                                                                         1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  1070 773   315         76       erythro-1,9-dioxo-15α-16-dihydroxy-1                                    -hy-                                                                          droxymethyl-2-nor-5-cis-13-trans-prosta-                                      diene,1-ethylene ketal                        1071 773   315         69       threo-1,9-dioxo-15α,16-dihydroxy-1-h                                    ydr-                                                                          oxymethyl-2-nor-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                          1072 773   315         74       erythro-1,9-dioxo-15α-hydroxy-16-met                                    hoxy-                                                                         1-hydroxymethyl-2-nor-5-cis-13-trans-                                         prostadiene,1-ethylene ketal                  1073 773   315        107       1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                       nor-5-cis-13-trans-prostadiene,1-ethyl-                                       ene ketal                                     1074 773   315        130       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     v                                                                             methyl-2-nor-5-cis-13-trans-prostadiene,-                                     e                                                                             1-ethylene ketal                              1075 773   315        134       1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     r                                                                             methyl-2-nor-5-cis-13-trans-17-trans-                                         prostatriene,1-ethylene ketal                 1076 774   315        186       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                    pent-                                                                         anor-16-phenoxy-5-cis-13-trans-prostadi-                                      ene,1-ethylene ketal                          1077 774   315        180       1,9-dioxo-15α-hydroxy-2,17,18,19,20-                                    pent-                                                                         anor-16-m-trifluoromethylphenoxy-1-hydr-                                      oxy-5-cis-13-trans-prostadiene,1-ethylene                                     i                                                                             ketal                                         1078 774   315        194       1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                      methyl-2-nor-5-cis-13-trans-prostadiene-                                      1-ethylene ketal                              1079 774   315        198       1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                     n                                                                             droxymethyl-2-nor-5-cis-13-trans-prosta-                                      diene,1-ethylene ketal                        1080 774   315         186b     1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                    ra-                                                                           nor-17-phenyl-1-hydroxymethyl-5-cis-13-                                       trans-prostadiene,1-ethylene ketal            1081 773   315         186e     1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                    ra-                                                                           nor-17-(m-trifluorophenyl)-1-hydroxymeth-                                     Z                                                                             yl-5-cis-13-trans-prostadiene,1-ethylene                                      ketal                                         1082 773   315         186d     1,9-dioxo-15α-hydroxy-2,18,19,20-tet                                    ra-                                                                           nor-17-(p-methoxyphenyl)-1-hydroxymeth-                                       yl-5-cis-13-trans-prostadiene,1-ethylene                                      ketal                                         __________________________________________________________________________

EXAMPLES 1083-1105

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 45 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table45. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymetri carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 45                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                          1,9-dioxo-1-hydroxymethylprostene and           Example                                                                            Example                                                                             of Example Example its diastereomer                                __________________________________________________________________________    1083 773   314        246     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     tetramethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-5-cis-13-trans-prostadi-                                        ene,1-ethylene ketal                            1084 774   314        245     nat-(and ent)-1,9-dioxo-16-hydroxy-16,17-                                     tetramethylene-18,19,20-trinor-1-hydr-                                        oxymethyl-5-cis-13-trans-prostadiene,1-                                       ethylene ketal                                  1085 773   314        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-5-cis-13-trans-prostadiene,1-eth-                                      ylene ketal                                     1086 773   314        243     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-13-trans-5-cis-prostadiene,1-eth-                                      ylene ketal                                     1087 773   314        251     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-1-hydroxy-                                      methyl-13-trans-5-cis-prostadiene,1-eth-                                      ylene ketal                                     1088 773   314        247     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     trimethylene-17,18,19,20-tetranor-1-hy-                                       droxymethyl-13-trans-5-cis-prostadiene,-                                      1-ethylene ketal                                1089 774   314        248     nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     pentamethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            1090 773   314        249     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene,1-eth-                                      ylene ketal                                     1091 773   314        250     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-5-cis-prostadiene,1-eth-                                      ylene ketal                                     1092 773   314        252     nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene,1-                                       ethylene ketal                                  1093 773   314        253     nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-5-cis-prostadiene,1-                                       ethylene ketal                                  1094 774   314        254     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene,1-ethylene ketal                         1095 774   314        255     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-17,18,19,20-tetra-                                       nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene,1-ethylene ketal                         1096 774   314        256     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(4-flu-                                      orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      oxymethyl-13-trans-5-cis-prostadiene,1-                                       ethylene ketal                                  1097 774   314        257     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(4-flu-                                      orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      oxymethyl-13-trans-5-cis-prostadiene,1-                                       ethylene ketal                                  1098 774   314        258     nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            1099 774   314        259     nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            1100 773   314        260     nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene,1-ethylene ketal                         1101 773   314        261     nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-5-cis-prost-                                     adiene,1-ethylene ketal                         1102 774   314        262     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-20-methyl-                                      1-hydroxymethyl-1-trans-5-cis-prostadi-                                       ene,1-ethylene ketal                            1103 774   314        263     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-20-methyl-                                      1-hydroxymethyl-13-trans-5-cis-prostadi-                                      ene,1-ethylene ketal                            1104 774   314        264     nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            1105 774   314        265     nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      16-hydroxy-16,17-trimethylene-16-(3-tri-                                      fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-5-cis-prostadi-                                        ene,1-ethylene ketal                            __________________________________________________________________________

EXAMPLES 1106-1189

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 46 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C₁₅ or C₁₆ positions,only the C₁₅ or C₁₆ -normal isomers are listed in Table 46; it should beunderstood that the corresponding C₁₅ or C₁₆ -epi isomers are alsoformed and are part of this invention.

In those cases where the initial conjugate-addition product contains atriphenylmethoxy blocking group, deblocking is conducted in aceticacid-tetrahydrofuran-water 4:2:1 at 50° C. for 5 hours.

                                      TABLE 46                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of        Vinyl Tin of                                            Example                                                                            Example                                                                             Cyclopent-2-en-1-one                                                                     Example    1,9-dioxo-1-hydroxymethylprostene            __________________________________________________________________________    1106 773   283        49         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16-                                      N                                                                             16-trimethylene-20-nor-13-trans-prostadi-                                     O                                                                             ene,1-ethylene-ketal                         1107 773   283        50         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     2                                                                             16-trimethylene-20-methyl-13-trans-prost-                                     .                                                                             adiene,1-ethylene ketal                      1108 773   283        51         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     u                                                                             16-trimethylene-20-ethyl-13-trans-prosta-                                     p                                                                             diene,1-ethylene-ketal                       1109 774   283        193        1,9-dioxo-16-hydroxy-16-cyclopropyl-1-20-                                     a                                                                             ethyl-1-hydroxymethyl-13-trans-prostene,-                                     r                                                                             1-ethylene ketal                             1110 774   283        195        1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1-                                     w                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                      .                                                                             ene ketal                                    1111 774   283        192        1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy-                                     Z                                                                             droxymethyl-13-trans-prostene,1-ethylene                                      5                                                                             ketal                                        1112 773   283        13         1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,-                                     3                                                                             16-trimethylene-13-trans-prostene,1-ethyl                                     -                                                                             ene ketal                                    1113 774   283        210a       1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-                                      h                                                                             vinyl-13-trans-prostene,1-ethylene                                            ketal                                        1114 773   283        74         dl-erythro-1,9-dioxo-15-hydroxy-16-meth-                                      o                                                                             oxy-1-hydroxymethyl-13-trans-prostene,1-                                      a                                                                             ethylene ketal                               1115 773   283        77         dl-erythro-1,9-dioxo-15-hydroxy-16-ethoxy                                     -                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      f                                                                             ylene ketal                                  1116 773   283        83         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-nor-13-trans-prostene,-                                      N                                                                             1-ethylene ketal                             1117 773   283        84         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-20-methyl-13-trans-prost-                                       ene,1-ethylene ketal                         1118 773   283        85         dl-erythro-1,9-dioxo-15,16-dihydroxo-1-                                       hydroxymethyl-20-ethyl-13-trans-prost-                                        ene,1-ethylene ketal                         1119 773   283        86         dl-erythro-1,9-dioxo-15,16-dihydroxy-19-                                      O                                                                             methyl-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                         1120 773   283        87         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-13-trans-17-trans-prosta-                                       diene,1-ethylene ketal                       1121 773   283        69         dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      r                                                                             droxymethyl-13-trans-prostene,1-ethylene                                      o                                                                             ketal                                        1122 773   283        88         dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        nor-1-hydroxymethyl-13-trans-prostene,-                                       1-ethylene ketal                             1123 773   283        76         dl-erythro-1,9-dioxo-15,16-dihydroxy-1-                                       hydroxymethyl-13-trans-prostene,1-ethyl-                                      s                                                                             ene ketal                                    1124 773   283        89         dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        methyl-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                         1125 773   283        90         dl-threo-1,9-dioxo-15,16-dihydroxy-20-                                        ethyl-1-hydroxymethyl-13-trans-prost-                                         ene,1-ethylene ketal                         1126 773   283        91         dl-threo-1,9-dioxo-15,16-dihydroxy-19-                                        methyl-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                         1127 773   283        92         dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy-                                      t                                                                             droxymethyl-13-trans-17-trans-prostadi-                                       ene,1-ethylene ketal                         1128 773   283        107        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      .                                                                             trans-prostene,1-ethylene ketal              1129 773   283        108        1,9-dioxo-16-hydroxy-1-hydroxymethyl-19,-                                     Z                                                                             20-dinor-13-trans-prostene,1-ethylene                                         ketal                                        1130 773   283        109        1,9-dioxo-16-hydroxy-1-hydroxymethyl-18,-                                     5                                                                             19,20-trinor-13-trans-prostene,1-ethylene                                     4                                                                             ketal                                        1131 773   283        110        1,9-dioxo-16-hydroxy-1-hydroxymethyl-20-                                      .                                                                             nor-13-trans-prostene,1-ethylene ketal       1132 773   283        144        1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy-                                     c                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1133 773   283        112        1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy                                      u                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1134 773   283        113        1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy                                       methyl-13-trans-prostene,1-ethylene                                           ketal                                        1135 773   283        139a       1,9-dioxo-16-hydroxy-16-methyl-20-ethyl-                                      b                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      e                                                                             ylene ketal                                  1136 773   283        115        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      r                                                                             trans-17-cis-prostadiene,1-ethylene                                           ketal                                        1137 773   283        135        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     o                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1138 773   283        136        1,9-dioxo-16-hydroxy-17,17,20-trimethyl-                                      o                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      t                                                                             ylene ketal                                  1139 773   283        137        1,9-dioxo-16-hydroxy-16,20-dimethyl-1-hy-                                     .                                                                             droxymethyl-13-trans-prostene,1-ethylene                                      Z                                                                             ketal                                        1140 773   283        138        1,9-dioxo-16-hydroxy-17,17-dimethyl-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                      5                                                                             ene ketal                                    1141 773   283        139        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     5                                                                             methyl-13-trans-17-trans-prostadiene,1-                                       ethylene ketal                               1142 773   283        149        1,9-dioxo-16-hydroxy-20-methyl-1-hydroxy-                                     {                                                                             methyl-13-trans-17-trans-prostadiene,1-                                       ethylene ketal                               1143 773   283        150        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     Z                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1144 773   283        151        1,9-dioxo-16-hydroxy-17,20-dimethyl-1-hy-                                     5                                                                             droxymethyl-13-trans-prostene,1-ethylene                                      6                                                                             ketal                                        1145 773   283        152        1,9-dioxo-16-hydroxy-1-hydroxymethyl-13-                                      }                                                                             trans-17-trans-prostadiene,1-ethylene                                         ketal                                        1146 773   283        153        1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl-                                      Z                                                                             13-trans-prostene,1-ethylene ketal           1147 773   283        154        1,9-dioxo-16(S)-hydroxy-1-hydroxymethyl-                                      5                                                                             13-trans-prostene,1-ethylene ketal           1148 773   283        148a       1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy-                                      N                                                                             methyl-13-trans-17-trans-prostadiene,1-                                       ethylene ketal                               1149 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymeth                                     yl-                                                                ylmethoxy-1-trans-                                                                       13-trans-prostadiene,1-ethylene ketal                              octene (U.S. Pat.                                                             No. 3,873,607).                                         1150 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-methyl-1-h                                     ydr-                                                               ylmethoxy-1-trans-                                                                       oxymethyl-13-trans-prostene,1-ethylene                             nonene (U.S. Pat.                                                                        ketal                                                              No. 3,873,607).                                         1151 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-20-ethyl-1-hy                                     dr-                                                                ylmethoxy-1-trans-                                                                       oxymethyl-13-trans-prostene,1-ethylene                             decene (U.S. Pat.                                                                        ketal                                                              No. 3,873,607).                                         1152 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethy                                     l-1-                                                               ylmethoxy-4,4-di-                                                                        hydroxymethyl-13-trans-prostene,1-eth-                             methyl-1-trans-                                                                          ylene ketal                                                        octene (U.S. Pat.                                                             No. 3,873,607).                                         1153 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,17-dimethy                                     l-1-                                                               ylmethoxy-5,5-di-                                                                        hydroxymethyl-13-trans-prostene,1-eth-                             methyl-1-trans-                                                                          ylene ketal                                                        octene (U.S. Pat.                                                             No. 3,873,607).                                         1154 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-methyl-1-h                                     ydr-                                                               ylmethoxy-4-meth-                                                                        oxymethyl-13-trans-prostene,1-ethylene                             yl-1-trans-octene                                                                        ketal                                                              (U.S. Pat. No.                                                                3,876,690).                                             1155 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16-ethyl-1-hy                                     dr-                                                                ylmethoxy-4-ethyl-                                                                       oxymethyl-13-trans-prostene,1-ethylene                             1-trans-octene                                                                           ketal                                                              (U.S. Pat. No.                                                                3,876,690).                                             1156 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-17,20-tetrano                                     r-                                                                 ylmethoxy-4-cyclo-                                                                       16-cyclopentyl-1-hydroxymethyl-13-trans-                                      5                                                                  pentyl-1-trans-                                                                          prostene,1-ethylene ketal                                          butene (U.S. Pat.                                                             No. 3,884,969).                                         1157 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,20-pentano                                     r-18-                                                              ylmethoxy-3-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-13-trans-                               hexyl-1-trans-                                                                           prostene,1-ethylene ketal                                          pentene (U.S. Pat.                                                            No. 3,884,969).                                         1158 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-18,20-trinor-                                     17-                                                                ylmethoxy-5-cyclo-                                                                       cyclohexyl-1-hydroxymethyl-13-trans-                               hexyl-1-trans-                                                                           prostene,1-ethylene ketal                                          pentene (U.S. Pat.                                                            No. 3,884,969).                                         1159 773   283        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-19,20-dinor-1                                     8-                                                                 ylmethoxy-6-cyclo-                                                                       cyclopentyl-1-hydroxymethyl-13-trans-                              pentyl-1-trans-                                                                          prostene,1-ethylene ketal                                          hexene (U.S. Pat.                                                             No. 3,884,969).                                         1160 773   283        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-1-h                                     ydr-                                                               trimethylsilyl-                                                                          oxymethyl-13-trans-prostene,1-ethylene                             oxy-trans-1-octene                                                                       ketal                                                              (Example 125).                                          1161 773   283        1-iodo-3-methyl-3-                                                                       1,9-dioxo-15α-hydroxy-15-methyl-20-                                     eth-                                                               trimethylsilyl-                                                                          yl-1-hydroxymethyl-13-trans-prostene,1-                            oxy-trans-1-decene                                                                       ethylene ketal                                                     (Example 190a).                                         1162 774   283        159        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-fluorophenoxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal           1163 774   283        186        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-phenoxy-1-hydroxymethyl-13-trans-                                      a                                                                             prostene,1-ethylene ketal                    1164 774   283        181        1,9-dioxo-15α -hydroxy-17,18,19,20-                                     tetra-                                                                        nor-16-p-bromophenoxy-1-hydroxymethyl-13-                                     u                                                                             trans-prostene,1-ethylene ketal              1165 774   283        182        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-t-butylphenoxy-1-hydroxymethyl-                                      e                                                                             13-trans-prostene,1-ethylene ketal           1166 774   283        183        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-methoxyphenoxy-1-hydroxymethyl-                                      Z                                                                             13-trans-prostene,1-ethylene ketal           1167 774   283        184        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-p-chlorophenoxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal           1168 774   283        180        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-m-trifluorophenoxy-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal           1169 774   283        185        1,9-dioxo-15α-hydroxy-17,18,19,20-t                                     etra-                                                                         nor-16-(3,4-dichlorophenoxy)-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene                                           ketal                                        1170 774   283        186b       1,9-dioxo-15α-hydroxy-18,19,20-trin                                     or-17-                                                                        phenyl-1-hydroxymethyl-13-trans-prost-                                        ene,1-ethylene ketal                         1171 774   283        186e       1,9-dioxo-15α-hydroxy-18,19,20-trin                                     or-17-                                                                        (m-trifluoromethylphenyl)-1-hydroxymeth-                                      g                                                                             yl-13-trans-prostene,1-ethylene ketal        1172 774   283        186d       1,9-dioxo-15α-hydroxy-18,19,20-trin                                     or-1-                                                                         (p-methoxyphenyl)-1-hydroxymethyl-13-                                         trans-prostene,1-ethylene ketal              1173 773   310        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-1-hydroxymeth                                     yl-2-                                                              ylmethoxy-1-trans-                                                                       nor-13-trans-prostene,1-ethylene ketal                             octene (U.S. Pat.                                                             No. 3,873,607).                                         1174 773   310        185        1,9-dioxo-15α-hydroxy-15-methyl-1-h                                     ydr-                                                                          oxymethyl-2-nor-13-trans-prostene,1-eth-                                      i                                                                             ylene ketal                                  1175 773   310        1-iodo-3-triphen-                                                                        1,9-dioxo-15α-hydroxy-16,16-dimethy                                     l-1-                                                               ylmethoxy-5,5-di-                                                                        hydroxymethyl-2-nor-13-trans-prostene,                             methyl-octene                                                                            1-ethylene ketal                                                   (U.S. Pat. No.                                                                3,873,607).                                             1176 773   310        13         1,9-dioxo-15α-hydroxy-16,16-trimeth                                     ylene-                                                                        1-hydroxymethyl-2-nor-13-trans-prostene,-                                     t                                                                             1-ethylene ketal                             1177 773   310        76         erythro-1,9-dioxo-15α,16-dihydroxy-                                     1-hy-                                                                         droxymethyl-2-nor-13-trans-prostene,1-                                        ethylene ketal                               1178 773   310        69         threo-1,9-dioxo-15α,16-dihydroxy-1-                                     hydr-                                                                         oxymethyl-2-nor-13-trans-prostene,1-eth-                                      6                                                                             ylene ketal                                  1179 773   310        74         erythro-1,9-dioxo-15α-hydroxy-16-me                                     thoxy-                                                                        1-hydroxymethyl-2-nor-13-trans-prostene,                                      .                                                                             1-ethylene ketal                             1180 773   310        107        1,9-dioxo-16-hydroxy-1-hydroxymethyl-2-                                       nor-13-trans-prostene,1-ethylene ketal       1181 773   285        130        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     a                                                                             methyl-2-nor-13-trans-prostene,1-ethylene                                     l                                                                             ketal                                        1182 773   285        134        1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy-                                     p                                                                             methyl-2-nor-13-trans-17-trans-prostadi-                                      h                                                                             ene,1-ethylene ketal                         1183 774   285        186        1,9-dioxo-15α-hydroxy-2,17,18,19-20                                     -                                                                             pentanor-16-phenoxy-1-hydroxymethyl-13-                                       trans-prostene,1-ethylene ketal              1184 774   285        180        1,9-dioxo-15α-hydroxy-2,17,18,19,20                                     -                                                                             pentanor-16-m-trifluoromethylphenoxy-1-                                       hydroxymethyl-13-trans-prostene,1-ethyl-                                      Z                                                                             ene ketal                                    1185 773   285        194        1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxy-                                      6                                                                             methyl-2-nor-13-trans-prostene,1-ethylene                                     1                                                                             ketal                                        1186 774   285        198        1,9-dioxo-16-hydroxy-16-cyclopropyl-1-                                        hydroxymethyl-2-nor-13-trans-prostene,-                                       1-ethylene ketal                             1187 774   285        186b       1,9-dioxo-15α-hydroxy-2,18,19,20-te                                     tranor-                                                                       17-phenyl-1-hydroxymethyl-13-trans-pro-                                       stene,1-ethylene ketal                       1188 773   285        186e       1,9-dioxo-15α-hydroxy-2,18,19,20-te                                     tranor-                                                                       17-(m-trifluorophenyl)-1-hydroxymethyl-                                       13-trans-prostene,1-ethylene ketal           1189 773   285        186d       1,9-dioxo-15α-hydroxy-2,18,19,20-te                                     tranor-                                                                       17-(p-methoxyphenyl)-1-hydroxymethyl-                                         trans-prostene,1-ethylene                    __________________________________________________________________________                                     ketal                                    

EXAMPLES 1190-1212

By the methods described hereinabove in Examples 773 and 774, the1,9-dioxo-1-hydroxymethyl prostene derivative shown in Table 47 areprepared by the indicated method from the indicated vinyl iodide orvinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in theconjugate-addition, only one of the diastereoisomers is listed in Table47. It should be understood that the other diastereoisomer is alsoformed which in its nat and ent forms has an opposite (mirror image)configuration at the assymmetri carbon atoms on the β-chain (the chaincontaining C₁₃ . . . C₁₄ etc.) to that of the respective nat and entforms of the listed diastereoisomer; both of these diastereoisomers areclaimed in this invention as well as their component enantiomers.

                                      TABLE 47                                    __________________________________________________________________________                          Vinyl Iodide or                                              Method of                                                                           Cyclopent-2-en-1-one                                                                     Vinyl Tin of                                                                             1,9-dioxo-1-hydroxymethylprostene and        Example                                                                            Example                                                                             of Example Example    its diastereomer                             __________________________________________________________________________    1190 773   283        246        nat-(and ent)-1,9-dioxo-16-hydroxy-15,16-                                     N                                                                             tetramethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                      O                                                                             ene ketal                                    1191 774   283        245        nat-(and ent)-1,9-dioxo-16-hydroxy-16-                                        tetramethylene-18,19,20-trinor-1-hydroxy-                                     m                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1192 773   283        243        nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      .                                                                             15-hydroxy-15,16-trimethylene-1-hydroxy-                                      Z                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1193 773   283        243        nat-15S,16R-(and ent-15R,16S)-1,9-dioxo-                                      6                                                                             15-hydroxy-15,16-trimethylene-1-hydroxy-                                      2                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1194 773   283        251        nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      .                                                                             15-hydroxy-15,16-trimethylene-1-hydroxy-                                      b                                                                             methyl-13-trans-prostene,1-ethylene                                           ketal                                        1195 773   283        247        nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     e                                                                             trimethylene-17,18,19,20-tetranor-1-hydr-                                     t                                                                             oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                        1196 773   283        248        nat-(and ent)-1,9-dioxo-15-hydroxy-15,16-                                     a                                                                             pentamethylene-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                      .                                                                             ene ketal                                    1197 773   283        249        nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      Z                                                                             15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene                                           ketal                                        1198 773   283        250        nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      6                                                                             15-hydroxy-15,17-dimethylene-1-hydroxy-                                       methyl-13-trans-prostene,1-ethylene                                           ketal                                        1199 773   283        252        nat-15S,16R-(and ent-15R,16S-1,9-dioxo-                                       15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                        1200 773   283        253        nat-15S,16S-(and ent-15R,16R)-1,9-dioxo-                                      3                                                                             15-hydroxy-15,16-tetramethylene-1-hydr-                                       oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                        1201 774   283        254        nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      .                                                                             15-hydroxy-15,16-trimethylene-16-(3-tri-                                      c                                                                             fluoromethylphenoxy)-17,18,19,20-tetranor                                     -                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      c                                                                             ylene ketal                                  1202 774   283        255        nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      l                                                                             15-hydroxy-15,16-trimethylene-16-(3-tri-                                      b                                                                             fluoromethylphenoxy)-17,18,19,20-tetranor                                     -                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      r                                                                             ylene ketal                                  1203 773   283        256        nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      .                                                                             15-hydroxy-15,16-trimethylene-16-(4-flu-                                      Z                                                                             orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      6                                                                             oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                        1204 773   283        257        nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      4                                                                             15-hydroxy-15,16-trimethylene-16-(4-flu-                                      .                                                                             orophenoxy)-17,18,19,20-tetranor-1-hydr-                                      G                                                                             oxymethyl-13-trans-prostene,1-ethylene                                        ketal                                        1205 774   283        258        nat-15R,16S-(and ent-15S,16R)-1,9-dioxo-                                      A                                                                             15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                      M                                                                             ene ketal                                    1206 774   283        259        nat-15R,16R-(and ent-15S,16S)-1,9-dioxo-                                      M                                                                             15-hydroxy-15,16-trimethylene-16-(3-                                          chlorophenoxy)-17,18,19,20-tetranor-1-                                        hydroxymethyl-13-trans-prostene,1-ethyl-                                      A                                                                             ene ketal                                    1207 773   283        260        nat-15S,17R-(and ent-15R,17S)-1,9-dioxo-                                      .                                                                             15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-prostene,1-                                      N                                                                             ethylene ketal                               1208 773   283        261        nat-15S,17S-(and ent-15R,17R)-1,9-dioxo-                                      O                                                                             15-hydroxy-15,17-trimethylene-19,20-di-                                       nor-1-hydroxymethyl-13-trans-prostene,1-                                      Z                                                                             ethylene ketal                               1209 774   283        262        nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      6                                                                             16-hydroxy-16,17-trimethylene-20-methyl-                                      5                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      .                                                                             ylene ketal                                  1210 774   283        263        nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      g                                                                             16-hydroxy-16,17-trimethylene-20-methyl-                                      a                                                                             1-hydroxymethyl-13-trans-prostene,1-eth-                                      m                                                                             ylene ketal                                  1211 774   283        264        nat-16R,17S-(and ent-16S,17R)-1,9-dioxo-                                      m                                                                             16-hydroxy-16,17-trimethylene-16-(3-tri-                                      a                                                                             fluoromethylphenoxy)-18,19,20-trinor-1-                                       hydroxymethyl-13-trans-prostene,1-ethyl-                                      .                                                                             ene ketal                                    1212 774   283        265        nat-16R,17R-(and ent-16S,17S)-1,9-dioxo-                                      Z                                                                             16-hydroxy-16,17-trimethylene-16-(3-tri-                                      6                                                                             fluoromethylphenoxy)-18,19,20,-trinor-1-                                      6                                                                             hydroxymethyl-13-trans-prostene,1-ethyl-                                      .                                                                             ene ketal                                    __________________________________________________________________________

EXAMPLE 12131,9-Dioxo-11α,16-dihydroxy-16-vinyl-1-acetoxymethyl-5-cis-13-transprostadiene

To a solution of 0.1 g of1,9-dioxo-11α,16-dihydroxy-16-vinyl-1-hydroxymethyl-5-cis-13-transprostadiene in 0.75 ml of pyridine is added 0.026 g of acetic anhydride.After standing overnight, the pyridine is removed at reduced pressure.The residue is chromatographed on a dry column of silica gel elutingwith benzene-ethylacetate 1:1 to give 0.049 g of the product.

In accordance with the above example 1213 the 1-hydroxymethyl analogs ofExamples 319-769 are treated with acetic anhydride, propionic anhydride,n-butyric anhydride and n-valeric anhydride to give the respective1-acetoxymethyl, 1-propoxymethyl, 1-n-butoxymethyl and 1-n-peutoxymethylanalogs.

EXAMPLE 1214 Preparation of1-oxo-9β,11α,16-trihydroxy-1-hydroxymethyl-16-vinyl 13 trans-prosteneand 1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-vinyl 13-transprostene

To a solution of 2.9 g. (5.6 mmol) of (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-butylstannylactene (Ex. 210a) in 4ml. of tetrahydrofuran at 78° C. under argon with stirring is added 2.4ml of 2.4M n-butyllithium in hexane. The solution is stirred at -30° to-20° C. for 2 hr. A solution of 0.74 g (5.6 mmol) of copper pentyne and2.3 ml of hexamethylphosphoroustriamide in 18 ml of ether is added at-78° C. The solution is stirred at -78° C. for 1.5 hr. A solution of 2.0g (5.2 mmol) of1-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl)hexenyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-1-onein 20 ml of ether is added. The solution is stirred at -30° to -20° for1.5 hr. To the solution is added 100 ml of saturated ammonium chloride.The mixture is extracted with ether and the ether solution is washedwith dilute hydrochloric acid, saturated sodium bicarbonate, and driedover magnesium sulfate. Dry solvent is removed and the residue isdissolved in 30 Ml of ethanol and 0.37 g of sodium borohydride is added.The mixture is stirred for 8 hr. The solvent is removed. The residue isdissolved in 90 ml of acetic acid-tetrahydrofuran-water 4:2:1. Thesolution is stirred at room temperature for 2 hr. The solvents are movedat reduced pressure. The residue is chromatographed on silica gel togive 1-oxo-9β,11α,16-trihydroxy-1-hydroxymethyl 16-vinyl 3trans-prostene and 1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-vinyl13 trans-prostene.

By the methods described hereinabove in example 1214 the vinyl iodidesor vinyl tin compounds used in examples 319-772 are exchanged witht-butyl lithium or n-butyllithium respectively to give the vinyl lithiumreagents which on reaction with copper pentyne and hexamethylphosphorous triamide give the cuprate reagents. Addition of thecyclopent-2-en-1-ones used in examples 319-772 at 78° followed bywarming to -20° as described hereinabove in example 1214 gives the 9-oxoanalogs in which the 1-oxo feature is still protected. The reaction ofthese with sodium borohydride in ethanol followed by deblocking withacetic acid tetrahydrofuran-water 4:2:1 or with dilute hydrochloric acidin tetrahydrofuran gives 1-oxo-9β-hydroxy and 1-oxo-9α-hydroxy analogscorresponding to the 1,9-droxo analogs of examples 319-772.

EXAMPLE 1215 Preparation of1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-methyl 13-trans prostene

To a solution of 3.4 (0.00675 mol) of (E) 4-trimethylsilyloxy4-methyl-1-tri-n-butylstannyloctene (Example 210b) in 3.5 ml oftetrahydrofuran at -78° under argon, with stirring is added 2.8 ml.(0.00675 mol) of 2.4 M n-butyllithium in hexane. The solution ismaintained at -15° to -20° for 2.5 hr. A solution of 0.89 g (0.00675mol) of copper pentyne and 2.2 g of hexamethyl phosphorous triamide in25 ml of ether is added at -78° . After 1 hr, a solution of 2.3 g (0.005mol) of1-(8-dimethyl-t-butylsilyloxy-7-oxooctenyl)-4-trimethylsilyloxycyclopent-2-en-1-one,7-ethylene petal in 10 ml of ether is added. The mixture is stirred at-45° for 0.5 hr. and allowed to warm to -20° over 40 min. The solutionis recooled to - 30° and 2.5 ml. of acetic acid followed by saturatedammonium chloride is added. The mixture is extracted with ether. Theether layer is worked with dilute hydrochloric acid followed bysaturated sodium bicarbonate. The solution is dried over magnesiumsulfate. The solvent is removed. The residue is dissolved in 10 ml ofether at -78° under argon with stirring is added 20 ml. (0.01 mol) of0.5M lithim perhydro-96-boropehnolyhydride in tetrahydrofuran. Thesolution is allowed to warm to 0° over 35 min. At 0° is added 8 g ofsodium carbonate in 60 ml of water followed by 13 ml. of 30% hydrogenperoxide. The mixture is stirred for 10 min. and then extracted withether. The ether solution is washed with water, saturated sodiumbisulfite, and saturated sodium bicarbonate. The solution is dried ofmagnesium sulfate. The residue is dissolved in 60 ml of tetrahydrofurancontaining 9.6 ml of water and 1.2 ml of concentrated hydrochloric acid.The solution is stirred at 55°-60° for 4 hr. 45 min. The mixture issaturated with sodium chloride and extracted with ethyl acetate. Theorganic layer is washed with saturated sodium bicarbonate and dried overmagnesium sulfate. The solvent is removed. The residue ischromatographed on a dry column of silica gel eluting with ethyl acetatecontaining 4% of methanol to give the title compound.

By the methods described hereinabove in example 1215 the vinyl iodidesor vinyl tin compounds used in examples 319-772 are exchanged witht-butyllithium or n-butyl lithium respectively to give the vinyl lithiumreagents which on reaction with copper pentyne and hexamethylphosphorous triamide give the cuprate reagents. Addition of thecyclopent-2-en-1-ones used in examples 319-772 at -78° followed bywarming to -20° as described hereinabove in example 1214 gives the 9-oxoanalogs in which the 1-oxo feature is still protected. The reaction ofthese with lithium perhydro-9b-boraphenolyhydride at -78° followed bywarming to 0°, quenching with sodium carbonate and hydrogen peroxide anddeblocking with acetic acid-tetrahydrofuran-water 4:2:1 or with dilutehydrochloric acid in tetrahydrofuran gives the 1-oxo-9α hydroxy analogscorresponding to the 1,9-dioxo analogs of examples 319-772.

EXAMPLE 1216 Preparation of1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16 methyl-13-trans prostene,1-ethylene ketal and1-oxo-9β,11α,16-trihydroxy-1-hydroxymethyl-16-methyl-13-transprostene,1-ethylene ketal

To a solution of 0.1 g. of1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-16-methyl-5-cis-13-transprostadiene, 1-ethylene ketal (Example 774) in 25 ml of ethanol is added0.1 g. of sodium borohydride. After stirring 3 hr. the mixture is pouredinto water and extracted with ethyl acetate. The ethyl acetate solutionis dried over magnesium sulfate. The solvent is removed and the titlecompounds are separated by silica gel chromatography.

By the method described hereinabove in example 1216 the1,9-dioxo,1-ethylene ketal analogs of examples 775-1212 are reacted withan excess of sodium borohydride in ethanol to give the corresponding9α-hydroxy-1-ethylene ketal and 9β-hydroxy-1-ethylene ketal analogs.

EXAMPLE 1217 Preparation of1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-methyl-10,13-trans-prostadiene.

To a solution of 0.1 g of 1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-1bmethyl-13-trans prostene in 4 ml of tetrahydrofuran is added 2 ml of1.5N hydrochloric acid. After 2 days the mixture is poured into waterand extracted with ether. The ether solution is dried over magnesiumsulfate and the ether is removed to give the title compound.

EXAMPLE 1218 Preparation of1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-methyl-10,13trans-prostadiene-1-ethylene ketal.

To a solution of 0.1 g of1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-16-methyl-13-transprostene-1-ethylene ketal in 4 ml of tetrahydrofuran is added 2 ml of1.5 N hydrochloric acid. After 2 days the mixture is poured into waterand extracted with ether. The ether solution is dried over magnesiumsulfate and the ether is removed to give the title compound.

EXAMPLE 1219 Preparation of 1,9-dioxo-16-hydroxy-1-acetoxymethyl 16methyl-10,13-trans-prostadiene

To a solution of 0.1 g of1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-methyl-10,13-trans-prostadiene(Example 1214) in 0.75 ml of pyridine is added 0.026 g of aceticanhydride. After 18 hr. at room temperature, the solvent is removed atreduced pressure and the residue is chromatographed on silica gel togive the title compound.

By the method described hereinabove in Examples 1214 and 1215 the11α-hydroxy analogs of examples 319-1213 were treated with 1.5Nhydrochloric acid in tetrahydrofuran for 2 days to give thecorresponding Δ10 compounds of this invention.

I claim:
 1. An optically active compound of the formula: ##STR145##wherein X is a divalent moiety selected from the group consisting of:##STR146## f is an integer from 5 to 7; inclusive; R₃ is selected fromthe group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ is ethyleneortrans-vinylene; R₁ is a radical selected from the group consisting of:##STR147## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is moiety selected from the group consisting of: ##STR148##wherein R₄ is selected from the group consisting of hydrogen and methyl,R₅ is selected from the group consisting of C₄ -C₇ alkyl, R₆ is selectedfrom the group consisting of C₃ -C₅ alkyl, R₇ is selected from the groupconsisting of C₂ -C₄ alkyl, R₈ is selected from the group consisting ofC₁ -C₂ alkyl, p is an integer from 0 to 3, and q is 1 or 2, R₁₀ isselected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected fromthe group consisting of C₃ -C₇ alkyl, R₁₂ is selected from the groupconsisting of C₁ -C₄ alkyl, R₁₃ is C₃ -C₆ alkyl, X is a divalent radicalselected from the group consisting of: ##STR149## wherein R₁₄ isselected from the group consisting of C₁ -C₇ alkyl, hydrogen and aphenoxy group optionally substituted from the group consisting ofhalogen, trifluoromethyl and C₁ -C₄ alkoxy, Y is a trivalent radicalselected from the group consisting of: ##STR150## Z is a divalentradical selected from the group consisting of --O--and --CH₂ -- -, m iszero or an integer from 1 to 4 inclusive, with the proviso that the sumof m and n has the value of 1 to 4, s is zero or the integer 1, t isselected from the group consisting of hydrogen, chloro, fluoro,dichloro, trifluoromethyl, methoxy and t-butyl; the racemic mixturethereof; and the mirror image thereof.
 2. An optically active compoundaccording to claim 1 of the formula: ##STR151## wherein X is a divalentmoiety selected from the group consisting of ##STR152## f is an integerfrom 5 to 7, inclusive; R₃ is selected from the group consisting ofhydrogen and hydroxyl; C₁₃ -C₁₄ is selected from the group consisting ofethylene and transvinylene; R₁ is a radical selected from the groupconsisting of ##STR153## wherein R is selected from the group consistingof C₁ -C₄ alkyl; R₂ is a moiety selected from the group consisting of##STR154## wherein R₄ is selected from the group consisting of hydrogenand methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl,R₆, is selected from the group consisting of C₃ -C₅ alkyl, R₇ isselected from the group consisting of C₂ -C₄, R₈ is selected from thegroup consisting of C₁ -C₂ alkyl, R₁₁ is selected from the groupconsisting of C₃ -C₇ alkyl, p is an integer from 0 to 3, and q is 1 or2; the racemic mixture thereof; and the mirror image thereof.
 3. Anoptically active compound according to claim 2, wherein f, R₂ and R₃ areas previously defined; C₁₃ -C₁₄ is trans-vinylene; R₁ is the moiety##STR155## and X is the divalent moiety ##STR156##
 4. An opticallyactive compound according to claim 2, wherein f, R₂ and R₃ are aspreviously defined; C₁₃ -C₁₄ is trans-vinylene; and R₁ is the moiety##STR157## wherein R is as previously defined; and X is the divalentmoiety ##STR158##
 5. An optically active compound according to claim 3wherein R₁,R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂ is amoiety selected from the group consisting of ##STR159## wherein R₄, R₅,R₆, R₈ and R₁₁ are as previously defined.
 6. An otpically activecompound according to claim 3, wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR160## wherein R₇,p and q are as previously defined.7. An optically active compound according to claim 6, wherein R₁, R₃,C₁₃ -C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR161## wherein p and q are aspreviously defined.
 8. The racemic compound according to claim 5,dl-1-oxo-9α, 11α, 15α-trihydroxy-1-hydroxymethyl-13-trans-prostene. 9.The racemic compound according to claim 5, dl-1-oxo-9α, 11α,15α-trihydroxy-1-hydroxymethyl-20-ethyl-13-trans-prostene.
 10. Theracemic compound according to claim 5, dl-1-oxo-9α, 11α,15α-trihydroxy-1-hydroxymethyl-16,16-dimethyl-13-trans-prostene.
 11. Theracemic compound according to claim 5,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-16-methyl-13-trans-prostene.12. The racemic compound according to claim 5, dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-prostene.13. The racemic compound according to claim 5, dl-1-oxo-9α, 11α,15α-trihydroxy-1-hydroxymethyl-16,16-trimethylene-20-ethyl-13-trans-prostene.14. The racemic compound according to claim 5, dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-15-methyl-13-trans-prostene
 15. Theracemic compound according to claim 5, dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-15-methyl-20-ethyl-13-trans-prostene.16. The racemic compound according to claim 5, dl-1-oxo-9α,15α-trihydroxymethyl-15-methyl-13-trans-prostene.
 17. The racemiccompound according to claim 5, dl-1-oxo-9α,15α-trihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-prostene. 18.The racemic compound according to claim 5, dl-1-oxo-9α,15α-dihydroxy-1-hydroxymethyl-13-trans-prostene.
 19. The racemiccompound according to claim 6, dl-1-oxo-9α, 11α,15α-trihydroxy-1-hydroxymethyl, 17,17-dimethyl-13-trans-prostene.
 20. Anoptically active compound according to claim 4, wherein R₁, R₃ C₁₃ -C₁₄,X and f are as previously defined; and R₂ is a moiety selected from thegroup consisting of ##STR162## wherein R₄, R₅, R₆, R₈ and R₁₁ are aspreviously defined.
 21. An optically active compound according to claim4, wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂is a moiety selected from the group consisting of ##STR163## wherein R₇,p and q are as previously defined.
 22. An optically active compoundaccording a claim 21 wherein R₁, R₃, C₁₃₋₁₄, X and f are as previouslydefined; and R is a moiety selected from the group consisting of##STR164## wherein p and q are as previously defined.
 23. The racemiccompound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-13-trans-prostene. 24.The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-20-ethyl-13-trans-prostene.25. The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-propoxymethyl-16,16-trimethylene-20-ethyl-13-trans-prostene.26. The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-15-methyl-13-trans-prostene.27. The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-n-butoxy-15-methyl-20-ethyl-13-trans-prostene.28. The racemic compound according to claim 20,dl-1-oxo-9α,15α-dihydroxy-acetoxymethyl-15-methyl-13-trans-prostene. 29.The racemic compound according to claim 20,dl-1-oxo-9α,15α-dihydroxy-1-acetoxymethyl-16,16-trimethylene-13-transprostene.
 30. The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-16,16-dimethyl-13-trans-prostene.31. The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-16-methyl-13-trans-prostene.32. The racemic compound according to claim 20,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-16,16-trimethylene-13-trans-prostene.33. The racemic compound according to claim 20,dl-1-oxo-9α,15α-dihydroxy-1-acetoxymethyl-13-trans-prostene.
 34. Theracemic compound according to claim 1,dl-1-oxo-9α,11α,15α-trihydroxy-1-n-pentoxymethyl-17,17-dimethyl-13-trans-prostene.35. An optically active compound according to claim 1 of the formula:##STR165## wherein X is a divalent moiety selected from the groupconsisting of ##STR166## f is an integer from 5 to 7, inclusive; R₃ isselected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ isselected from the group consisting of ethylene and trans-vinylene; R₁ isa radical selected from the group consisting of ##STR167## wherein R isselected from the group consisting of C₁ -C₄ alkyl; R₂ is a moietyselected from the group consisting of ##STR168## wherein R₄ is selectedfrom the group consisting of hydrogen and methyl, R₅ is selected fromthe group consisting of C₄ -C₇ alkyl, R₆ is selected from the groupconsisting of C₃ -C₅ alkyl, R₇ is selected from the group consisting ofC₂ -C₄, R₈ is selected from the group consisting of C₁ -C₂ alkyl, R₁₁ isselected from the group consisting of C₃ -C₇ alkyl, p is an integer from0 to 3, and q is 1 or 2; the racemic mixture thereof and the mirrorimage thereof.
 36. An optically active compound according to claim 35wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR169## and X is the divalent moiety##STR170##
 37. An optically active compound according to claim 35wherein f, X, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR171## wherein R is as previouslydefined; and X is the divalent moiety ##STR172##
 38. An optically activecompound according to claim 36 wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR173## wherein R₄, R₅, R₆, R₈ and R₁₁ are aspreviously defined.
 39. An optically active compound according to claim36 wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂is a moiety selected from the group consisting of ##STR174## wherein R₇,p and q are as previously defined.
 40. An optically active compoundaccording to claim 39, wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR175## wherein p and q are as previously defined. 41.The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 42. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 43. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-16,16-methyl-13-trans-prostene-1-ethyleneketal.
 44. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-16-methyl-13-trans-prostene-1-ethyleneketal.
 45. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-prostene-1-ethyleneketal.
 46. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-16,16-trimethylene-20-ethyl-13-trans-prostene-1-ethyleneketal.
 47. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-15-methyl-13-trans-prostene-1-ethyleneketal.
 48. The racemic compound according to claim 38,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-15-methyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 49. The racemic compound according to claim 38,dl-1-oxo-9α,15α-dihydroxy-1-hydroxymethyl-15-methyl-13-trans-prostene-1-ethyleneketal.
 50. The racemic compound according to claim 38,dl-1-oxo-9α,15α-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-prostene-1-ethyleneketal.
 51. The racemic compound according to claim 38,dl-1-oxo-9α,15α-dihydroxy-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 52. The racemic compound according to claim 39,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,17-dimethyl-13-trans-prostene-1-ethyleneketal.
 53. An optically active compound according to claim 1 of theformula: ##STR176## wherein X is a divalent moiety selected from thegroup consisting of ##STR177## f is an integer from 5 to 7, inclusive;R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃-C₁₄ is selected from the group consisting of ethylene andtrans-vinylene; R₁ is a radical selected from the group consisting of##STR178## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR179##wherein R₁₃ is selected from the group consisting of C₃ -C₆ alkyl, R₇ isselected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected fromthe group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the groupconsisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consistingof C₁ -C₄ alkyl; the racemic mixture thereof; and the mirror imagethereof.
 54. An optically active compound according to claim 53 whereinf, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ is trans-vinylene; R₁is the moiety ##STR180## and X is the divalent moiety ##STR181##
 55. Anoptically active compound according to claim 53 wherein f, R₂ and R₃ areas previously defined; C₁₃ -C₁₄ is trans-vinylene; R₁ is the moiety##STR182## wherein R is as previously defined; and X is the divalentmoiety ##STR183##
 56. An optically active compound according to claim54, wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined, and R₂is a moiety selected from the group consisting of ##STR184## wherein R₆,R₁₀, R₁₁ and R₁₂ are as previously defined.
 57. An optically activecompound according to claim 54 wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR185## wherein R₇ is as previously defined.
 58. Anoptically active compound according to claim 57, wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR186## wherein R₇ is as previouslydefined.
 59. An optically active compound according to claim 56, whereinR₁, R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂ is a moietyselected from the group consisting of ##STR187## wherein R₆, R₁₁ and R₁₂are as previously defined.
 60. An optically active compound according toclaim 56, wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined;and R₂ is a moiety selected from the group consisting of ##STR188##wherein R₁₀ and R₁₁ are as previously defined.
 61. The racemic compoundaccording to claim 56,dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-vinyl-13-trans-prostene.62. The racemic compound according to claim 56,dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-vinyl-20-ethyl-13-trans-prostene.63. The racemic compound according to claim 56,dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-cyclopropyl-13-trans-prostene.64. The racemic compound according to claim 56, -1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16-cyclopropyl-20-ethyl-13-trans-prostene.65. The racemic compound according to claim 56, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16-ethyl-13-trans-prostene.
 66. Theracemic compound according to claim 56, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16,20 -diethyl13-trans-prostene.
 67. Theracemic compound according to claim 56, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16-vinyl-13-trans-prostene.
 68. Theracemic compound according to claim 58, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-17-methyl-13-trans-prostene.
 69. Theracemic compound according to claim 58, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-17,20-dimethyl-13-trans-prostene.
 70. Theracemic compound according to claim 58, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-17-methyl-20-ethyl-13-trans-prostene. 71.The racemic compound according to claim 59, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-13-trans-prostene.
 72. The racemiccompound according to claim 59, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-20-ethyl-13-trans-prostene.
 73. Theracemic compound according to claim 59, dl-1-oxo-9α, 11α,16(R)-trihydroxy-1-hydroxymethyl-13-trans-prostene.
 74. The racemiccompound according to claim 59, dl-1-oxo-9α, 11α,16(S)-trihydroxy-1-hydroxymethyl-13-trans-prostene.
 75. The racemiccompound according to claim 59, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-17-trans-13-trans-prostadiene.
 76. Theracemic compound according to claim 59, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-20-ethyl-17-trans-13-trans-prostadiene.77. The racemic compound according to claim 60, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-methyl-13-trans-prostene.
 78. Theracemic compound according to claim 60, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-13-trans-prostene.79. The racemic compound according to claim 60, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16-methyl-17-trans-13-trans-prostadiene.80. The racemic compound according to claim 60, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-17-trans-13-trans-prostadiene.81. An optically active compound according to claim 55 wherein R₁, R₃,C₁₃ -C₁₄, X and f are as previously defined, and R₂ is a moiety selectedfrom the group consisting of ##STR189## wherein R₆, R₁₀, R₁₁ and R₁₂ areas previously defined.
 82. An optically active compound according toclaim 53, wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined;and R₂ is a moiety selected from the group consisting of ##STR190##wherein R₇ is as previously defined.
 83. An optically active compoundaccording to claim 82, wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR191## wherein R₇ is as previously defined.
 84. Anoptically active compound according to cliam 81, wherein R₁, R₃, C₁₂-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR192## wherein R₆, R₁₁ and R₁₂ are aspreviously defined.
 85. An optically active compound according to claim81, wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂is a moiety selected from the group consisting of ##STR193## wherein R₁₀and R₁₁ are as previously defined.
 86. The racemic compound according toclaim 81, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-vinyl-13-trans-prostene.
 87. Theracemic compound according to claim 81, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-vinyl-20-ethyl-13-trans-prostene. 88.The racemic compound according to claim 81, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-cyclopropyl-13-trans-prostene.
 89. Theracemic compound according to claim 81, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-cyclopropyl-20-ethyl-13-trans-prostene.90. The racemic compound according to claim 81, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-ethyl-13-trans-prostene.
 91. Theracemic compound according to claim 81, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16,20-diethyl-13-trans-prostene.
 92. Theracemic compound according to claim 81, dl-1-oxo-9α,16-dihydroxy-1-acetoxymethyl-16-vinyl-13-trans-prostene.
 93. The racemiccompound according to claim 83, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-17-methyl-13-trans-prostene.
 94. Theracemic compound according to claim 83, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-17,20-dimethyl-13-trans-prostene.
 95. Theracemic compound according to claim 83, dl-1-oxo-9α,11α,16-trihydroxy-1-acetoxymethyl-17-methyl-20-ethyl-13-trans-prostene. 96.The racemic compound according to claim 84, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-13-trans-prostene.
 97. The racemiccompound according to claim 84, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-20-ethyl-13-trans-prostene.
 98. Theracemic compound according to claim 84, dl-1-oxo-9α, 11α,16(R)-trihydroxy-1-acetoxymethyl-13-trans-prostene.
 99. The racemiccompound according to claim 84, dl-1-oxo-9α, 11α,16(S)-trihydroxy-1-acetoxymethyl-13-trans-prostene.
 100. The racemiccompound according to claim 84, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-17-trans-13-trans-prostadiene.
 101. Theracemic compound according to claim 84, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-20-ethyl-17-trans-13-trans-prostadiene.102. The racemic compound according to claim 85, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-methyl-13-trans-prostene.
 103. Theracemic compound according to claim 85, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-methyl-20-ethyl-13-trans-prostene. 104.The racemic compound according to claim 85, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-methyl-17-trans-13-trans-prostadiene.105. The racemic compound according to claim 85, dl-1-oxo-9α, 11α,16-trihydroxy-1-acetoxymethyl-16-methyl-20-ethyl-17-trans-13-trans-prostadiene.106. An optically active compound according to claim 1 of the formula:##STR194## wherein X is a divalent moiety selected from the groupconsisting of ##STR195## f is an integer from 5 to 7, inclusive; R₃ isselected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ isselected from the group consisting of ethylene and trans-vinylene; R₁ isa radical selected from the group consisting of ##STR196## wherein R isselected from the group consisting of C₁ -C₄ alkyl; R₂ is a moietyselected from the group consisting of ##STR197## wherein R₃ is selectedfrom the group consisting of C₃ -C₆ alkyl, R₇ is selected from the groupconsisting of C₂ -C₄ alkyl, R₁₀ is selected from the group consisting ofC₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyland R₁₂ is selected from the group consisting of C₁ -C₄ alkyl; theracemic mixture thereof; and the mirror image thereof.
 107. An opticallyactive compound according to claim 106, wherein f, R₂ and R₃ are aspreviously defined; C₁₃ -C₁₄ is trans-vinylene; R₁ is the moiety##STR198## and X is the divalent moiety ##STR199##
 108. An opticallyactive compound according to claim 106, wherein f, R and R₃ are aspreviously defined; C₁₃ -C₁₄ is trans-vinylene; R₁ is the moiety##STR200## wherein R is as previously defined; and X is the divalentmoiety ##STR201##
 109. An optically active compound according to claim107, wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined, and R₂is a moiety selected from the group consisting of ##STR202## wherein R₆,R₁₀, R₁₁ and R₁₂ are as previously defined.
 110. An optically activecompound according to claim 107, wherein R₁, R₃, C₁₃ -C₁₄, X and f areas previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR203## wherein R₇ is as previously defined.
 111. Anoptically active compound according to claim 110, wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR204## wherein R₇ is as previouslydefined.
 112. An optically active compound according to claim 109,wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂ is amoiety selected from the group consisting of ##STR205## wherein R₆, R₁₁and R₁₂ are as previously defined.
 113. An optically active compoundaccording to claim 109, wherein R₁, R₃, C₁₃ -C₁₄, X and f are aspreviously defined; and R₂ is a moiety selected from the groupconsisting of ##STR206## wherein R₁₀ and R₁₁ are as previously defined.114. The racemic compound according to claim 109, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-16-vinyl-13-trans-prostene-1-ethyleneketal.
 115. The racemic compound according to claim 109, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-vinyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 116. The racemic compound according to claim 109, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-cyclopropyl-13-trans-prostene-1-ethyleneketal.
 117. The racemic compound according to claim 109, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-cyclopropyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 118. The racemic compound according to claim 109, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-cyclopropyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 119. The racemic compound according to claim 109, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16,20-diethyl-13-trans-prostene-1-ethyleneketal.
 120. The racemic compound according to claim 109, dl-1-oxo-9α,16-dihydroxy-1-hydroxymethyl-16-vinyl-13-trans-prostene-1-ethyleneketal.
 121. The racemic compound according to claim 111, dl-1oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-17-methyl-13-trans-prostene-1-ethyleneketal.
 122. The racemic compound according to claim 111, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-17,20-dimethyl-13-trans-prostene-1-ethyleneketal.
 123. The racemic compound according to claim 111, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-17-methyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 124. The racemic compound according to claim 112, dl-1-oxo-9α,11α, 16-trihydroxy-1-hydroxymethyl-13-trans-prostene-1-ethylene ketal.125. The racemic compound according to claim 112, dl-1-oxo-9α, 11α,16-trihydroxy-1-hydroxymethyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 126. The racemic compound according to claim 112, dl-1-oxo-9α,11α, 16(R)-trihydroxy-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 127. The racemic compound according to claim 112, dl-1-oxo-9α,11α, 16(S)-trihydroxy-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 128. The racemic compound according to claim 112, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-17-trans-13-trans-prostadiene-1-ethyleneketal.
 129. The racemic compound according to claim 112, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-20-ethyl-17-trans-13-trans-prostadiene-1-ethyleneketal.
 130. The racemic compound according to claim 113, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-methyl-13-trans-prostene-1-ethyleneketal.
 131. The racemic compound according to claim 113, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymeythyl-16-methyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 132. The racemic compound according to claim 113, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-methyl-17-trans-13-trans-prostadiene-1-ethyleneketal.
 133. The racemic compound according to claim 113, dl-1-oxo-9α,11α,16-trihydroxy-1-hydroxymethyl-16-methyl-20-ethyl-17-trans-13-trans-prostadiene-1-ethyleneketal.
 134. An optically active compound according to claim 1 of theformula: ##STR207## wherein X is a divalent moiety selected from thegroup consisting of ##STR208## f is an integer from 5 to 7, inclusive;R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃-C₁₄ is selected from the group consisting of ethylene andtrans-vinylene; R is a radical selected from the group consisting of##STR209## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR210##wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ isselected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selectedfrom the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof;and the mirror image thereof.
 135. An optically active compoundaccording to claim 2, wherein f, R₂ and R₃ are as previously defined;C₁₃ -C₁₄ is trans-vinylene; R₁ is the moiety ##STR211## and X is thedivalent moiety ##STR212##
 136. An optically active compound accordingto claim 2, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR213## wherein R is as previouslydefined; and X is the divalent moiety ##STR214##
 137. An opticallyactive compound according to claim 135, wherein R₁, R₃, C₁₃ -C₁₄, X andf are as previously defined; and R₂ is a moiety selected from the groupconsisting of ##STR215## wherein R₁₁ is as previously defined.
 138. Anoptically active compound according to claim 135, wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR216## wherein R₆ and R₈ are aspreviously defined.
 139. The racemic compound according to claim 137,dl-erythro-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-13-trans-prostene.140. The racemic compound according to claim 137,dl-erythro-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-20-ethyl-13-trans-prostene.141. The racemic compound according to claim 137,dl-threo-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-13-trans-prostene.142. The racemic compound according to claim 137,dl-theo-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-20-ethyl-13-trans-prostene.143. The racemic compound according to claim 138,dl-erythro-9α,11α,15α-trihydroxy-1,9-dioxo-1-hydroxymethyl-16-methoxy-13-trans-prostene.144. An optically active compound according to claim 136 wherein R₁, R₃,C₁₃ -C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR217## wherein R₁₁ is as previouslydefined.
 145. An optically active compound according to claim 136,wherein R₁, R₃, C₁₃ -C₁₄, X and f are as previously defined; and R₂ is amoiety selected from the group consisting of ##STR218## wherein R₆ andR₈ are as previously defined.
 146. The racemic compound according toclaim 144,dl-erythro-9α,11α,15α,16-tetrahydroxy-1-oxo-1-n-propoxymethyl-13-trans-prostene.147. The racemic compound according to claim 144,dl-erythro-9α,11α,15α,16-tetrahydroxy-1oxo-1-acetoxymethyl-20-ethyl-13-trans-prostene.148. The racemic compound according to claim 144,dl-threo-9α,11α,15α,16-tetrahydroxy-1-oxo-1-acetoxymethyl-13-trans-prostene.149. The racemic compound according to claim 144,dl-threo-9α,11α,15α,16-tetrahydroxy-1-oxo-1-acetoxymethyl-20-ethyl-13-trans-prostene.150. The racemic compound according to claim 145,dl-erythro-9α,11α,15α-trihydroxy-1-oxo-1-acetoxymethyl-16-methoxy-13-trans-prostene.151. An optically active compound according to claim 1 of the formula:##STR219## wherein X is a divalent moiety selected from the groupconsisting of ##STR220## f is an integer from 5 to 7, inclusive; R₃ isselected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ isselected from the group consisting of ethylene and trans-vinylene; R₁ isa radical selected from the group consisting of ##STR221## wherein R isselected from the group consisting of C₁ -C₄ alkyl; R₂ is a moietyselected from the group consisting of ##STR222## wherein R₆ is selectedfrom the group consisting of C₃ -C₅ alkyl, R₈ is selected from the groupconsisting of C₁ -C₂ alkyl and R₁₁ is selected from the group consistingof C₃ -C₇ alkyl; the racemic mixture thereof; and the mirror imagethereof.
 152. An optically active compound according to claim 151,wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR223## and X is the divalent moiety##STR224##
 153. An optically active compound according to claim 151wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR225## wherein R is as previouslydefined; and X is the divalent moiety ##STR226##
 154. An opticallyactive compound according to claim 152, wherein R₁, R₃, C₁₃ -C₁₄, X andf are as previously defined; and R is a moiety selected from the groupconsisting of ##STR227## wherein R₁₁ is as previously defined.
 155. Anoptically active compound according to claim 152, wherein R₁, R₃, C₁₃-C₁₄, X and f are as previously defined; and R₂ is a moiety selectedfrom the group consisting of ##STR228## wherein R₆ and R₈ are aspreviously defined.
 156. The racemic compound according to claim 154,dl-erythro-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 157. The racemic compound according to claim 154,dl-erythro-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 158. The racemic compound according to claim 154,dl-threo-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 159. The racemic compound according to claim 154,dl-threo-9α,11α,15α,16-tetrahydroxy-1-oxo-1-hydroxymethyl-20-ethyl-13-trans-prostene-1-ethyleneketal.
 160. The racemic compound according to claim 155,dl-erythro-9α,11α,15α-trihydroxy-1-oxo-1-hydroxymethyl-16-methoxy-13-trans-prostene-1-ethyleneketal.
 161. An optically active compound according to claim 1 of theformula: ##STR229## wherein X is a divalent moiety selected from thegroup consisting of ##STR230## f is an integer from 5 to 7, inclusive;R₃ is selected from the group consisting of hydrogen and hydroxyl; C₁₃-C₁₄ is selected from the group consisting of ethylene andtrans-vinylene; R is a radical selected from the group consisting of##STR231## wherein R is selected from the group consisting of C₁ -C₄alkyl; R₂ is a moiety selected from the group consisting of ##STR232##wherein X is a divalent radical selected from the group consisting of##STR233## wherein R₁₄ is selected from the group consisting of C₁ -C₇alkyl, hydrogen and a phenoxy group optionally substituted from thegroup consisting of halogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is atrivalent radical selected from the group consisting of ##STR234## Z isa divalent radical selected from the group consisting of --O and --CH₂--, m is zero or an integer from 1 to 4, inclusive, n is zero or aninteger from 1 to 4, inclusive, with the proviso that the sum of m and nhas the value of 1 to 4, s is zero or the integer 1, t is selected fromthe group consisting of hydrogen, chloro, fluoro, dichloro,trifluoromethyl, methoxy and t-butyl; the racemic mixture thereof; andthe mirror image thereof.
 162. An optically active compound according toclaim 161, wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR235## and X is the divalent moiety##STR236##
 163. An optically active compound according to claim 161,wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR237## wherein R is as previouslydefined; and X is the divalent moiety ##STR238##
 164. The racemiccompound according to claim 162,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-trifluoromethylphenoxy-13-trans-prostene.165. The racemic compound according to claim 162,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-chlorophenoxy-13-trans-prostene.166. The racemic compound according to claim 162,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,20-tetranor-16-p-fluorophenoxy-13-trans-prostene.167. The racemic compound according to claim 162,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-18,20-trinor-17-phenyl-13-trans-prostene.168. The racemic compound according to claim 162, nat (andent)-1-oxo-9α,11α,15α-trihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-1-hydroxymethyl-13-trans-prostene.169. The racemic compound according to claim 162, nat (andent)-1-oxo-9α,11α,16-trihydroxy-16,17-tetramethylene18,19,20-trinor-1-hydroxymethyl-13-trans-prostene.
 170. The racemiccompound according to claim 162, nat-15S,16R (andent-15R,16S)-1-oxo-9α,11α,15-trihydroxy-15,16-trimethylene-1-hydroxymethyl-13-trans-prostene.
 171. The racemiccompound according to claim 162, nat-15S,16S (andent-15R,16R)-1-oxo-9α,11α,15-trihydroxy-15,16-trimethylene-1-hydroxymethyl-13-trans-prostene.172. The racemic compound according to claim 163,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-17,20-tetranor-16-m-trifluoromethylphenoxy-13-trans-prostene.173. The racemic compound according to claim 163,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-17,20-tetranor-16-m-chlorophenoxy-13-trans-prostene.174. The racemic compound according to claim 163,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-17,20-tetranor-16-p-fluorophenoxy-13-trans-prostene.175. The racemic compound according to claim 163,dl-1-oxo-9α,11α,15α-trihydroxy-1-acetoxymethyl-18,20-trinor-17-phenyl-13-trans-prostene.176. The racemic compound according to claim 163, nat (andent)-1-oxo-9α,11α,15-trihydroxy-15,16-tetramethylene-17,18,19,20-tetranor-1-acetoxymethyl-13-trans-prostene.177. The racemic compound according to claim 163, nat (andent)-1-oxo-9α,11α,16-trihydroxy-16,17-tetramethylene-18,19,20-trinor-1-acetoxymethyl-13-trans-prostene.178. The racemic compound according to claim 163, nat-15S,16R(andent-15R,16S)-1-oxo-9α,11α,15-trihydroxy-15,16-trimethylene-1-acetoxymethyl-13-trans-prostene.179. The racemic compound according to claim 163, nat-15S,16S(andent-15R,16R)-1-oxo-9α,11α,15-trihydroxy-15,16-trimethylene-1-acetoxymethyl-13-trans-prostene.180. An optically active compound according to claim 1 of the formula:##STR239## wherein X is a divalent moiety selected from the groupconsisting of ##STR240## f is an integer from 5 to 7, inclusive; R₃ isselected from the group consisting of hydrogen and hydroxyl; C₁₃ -C₁₄ isselected from the group consisting of ethylene and trans-vinylene; R₁ isa radical selected from the group consisting of ##STR241## wherein R isselected from the group consisting of C₁ -C₄ alkyl; R₂ is a moietyselected from the group consisting of ##STR242## wherein X is a divalentradical selected from the group consisting of ##STR243## wherein R₁₄ isselected from the group consisting of C₁ -C₇ alkyl, hydrogen and aphenoxy group optionally substituted from the group consisting ofhalogen, trifluoromethyl and C₁ -C₄ alkyloxy, Y is a trivalent radicalselected from the group consisting of ##STR244## Z is a divalent radicalselected from the group consisting of --O and --CH₂ --, m is zero or aninteger from 1 to 4, inclusive, n is zero or an integer from 1 to 4,inclusive, with the proviso that the sum of m and n has the value of 1to 4, s is zero or the integer 1, t is selected from the groupconsisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl,methoxy and t-butyl; the racemic mixture thereof; and the mirror imagethereof.
 181. An optically active compound according to claim 180,wherein f, R₂ and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR245## and X is the divalent moiety##STR246##
 182. An optically active compound according to claim 180,wherein f, R and R₃ are as previously defined; C₁₃ -C₁₄ istrans-vinylene; R₁ is the moiety ##STR247## wherein R is as previouslydefined; and X is the divalent moiety ##STR248##
 183. The racemiccompound according to claim 180,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-trifluoromethylphenoxy-13-trans-prostene-1-ethyleneketal.
 184. The racemic compound according to claim 180,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,20-tetranor-16-m-chlorophenoxy-13-trans-prostene-1-ethyleneketal.
 185. The racemic compound according to claim 180,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-17,20-tetranor-16-p-fluorophenoxy-13-trans-prostene-1-ethyleneketal.
 186. The racemic compound according to claim 180,dl-1-oxo-9α,11α,15α-trihydroxy-1-hydroxymethyl-18,20-trinor-17-phenyl-13-trans-prostene-1-ethyleneketal.
 187. The racemic compound according to claim 181, nat (andent)-1-oxo-9α,11α,15-trihydroxy-15,16-tetramethylene17,18,19,20-tetranor-1-hydroxymethyl-13-trans-prostene-1-ethylene ketal.188. The racemic compound according to claim 181, nat (andent)-1-oxo-9α,11α,16-trihydroxy-16,17-tetramethylene-18,19,20-trinor-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 189. The racemic compound according to claim 181, nat-15S,16R(andent-15R,16S)-1-oxo-9α,11α,15-trihydroxy-15,16-trimethylene-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.
 190. The racemic compound according to claim 181, nat-15S,16S(andent-15R,16R)-1-oxo-9α,11α,15-trihydroxy-15,16-trimethylene-1-hydroxymethyl-13-trans-prostene-1-ethyleneketal.